Cancer Research DKFZ 2013 PDF

GERMAN CANCER RESEARCH
CENTER IN THE HELMHOLTZ

ASSOCIATION
GERMAN CANCER RESEARCH CENTER
IN THE HELMHOLTZ ASSOCIATION
Cancer Research
at DKFZ
2013
Cancer Research
at DKFZ
2013
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Welcome
to the German Cancer Research Center
With Cancer Research at DKFZ, we would like to introduce the DKFZ (Deutsches Krebsforschungszentrum),
Germanys largest biomedical research center whose mission is to ght cancer through research. More than 3000
staff members, including 1000 scientists, contribute to unraveling the basic mechanisms that lead to cancer, iden-
tifying cancer risk factors, developing cancer prevention strategies, as well as translating our results from bench to
bedside in order to improve cancer diagnosis, therapy and prevention.
Cancer is a worldwide burden, with approximately 12.8 million new cases each year and around 7.6 million deaths
from cancer. The disease constitutes a particularly challenging task for both research and clinical practice. There are
more than 200 different cancer entities in almost every organ in the human body. The changes in affected cells are
highly diverse and complex.
In recent years, researchers at the DKFZ have made major contributions to both basic research and the development
of novel approaches for clinical application. These achievements received particular recognition in 2008, when the
former Director of our center, Harald zur Hausen, was awarded the Nobel Prize in Medicine for his outstanding disco-
very that human papilloma viruses play a critical role in the onset of cervical cancer.
Perhaps you too would like to be part of this unique institution at the cutting edge of cancer research. Cancer Re-
search at DKFZ" gives you a taste of what research is like in our center. Come and join us as a PhD student, Post Doc,
group leader or as a full Professor. We look forward to welcoming you to our institution.
Best wishes
Prof. Dr. Dr. h. c. Otmar D. Wiestler Prof. Dr. Josef Puchta
Chairman and Scientic Director Administrative-Commercial Director

Professor Josef Puchta (left) and Professor Otmar D. Wiestler.
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DKFZ The German Cancer Research Center ________________________
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NCT National Center for Tumor Diseases Heidelberg ________________
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The German Consortiom for Translational Cancer Research __________
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Nobel Prize in Medicine 2008 Harald zur Hausen _________________
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DKFZ Life-Science Lab __________________________________________
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Graduate Studies at the DKFZ ___________________________________
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Cancer Information Service _____________________________________
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Unit Cancer Prevention _________________________________________
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Heidelberg A Capital of Biomedical Sciences in Europe _____________
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CORE FACILITIES __________________________
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Genomics and Proteomics __________________________
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Imaging and Cytometry ____________________________
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Information Technology ____________________________
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Animal Laboratory Services _________________________
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Library ___________________________________________
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Joint Chemical Biology Core Facility of EMBL & DKFZ ____
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RESEARCH PROGRAMS ____________________________
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Cell Biology and Tumor Biology __________________________
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Stem Cells and Cancer _________________________________________
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Molecular Embryology _________________________________________
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Signal Transduction and Growth Control __________________________
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Epigenetik ___________________________________________________
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Systems Biology of Cellular Signal Transduction ____________________
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Redox Regulation______________________________________________
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Molecular Metabolic Control ____________________________________
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Vascular Oncology and Metastasis _______________________________
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Cell Growth and Proliferation ___________________________________
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Clinical Neurobiology __________________________________________
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Chaperones and Proteases ______________________________________
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Molecular Neurobiology ________________________________________
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Molecular Biology of the Cell II __________________________________
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Cell Biology __________________________________________________
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Molecular Biology of the Cell I ___________________________________
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Molecular Biology of Centrosomes and Cilia _______________________
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Posttranscriptional Control of Gene Expression ____________________
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Cellular Senescence____________________________________________
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Normal and Neoplastic CNS Stem Cells ___________________________
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Vascular Signaling and Cancer ___________________________________
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Stress-induced Activation of Hematopoietic Stem Cells ______________
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Experimental Hematology ______________________________________
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Biomarker identication ________________________________________
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Metastatic Niches _____________________________________________
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Synaptic Signalling and Neurodegeneration _______________________
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Functional and Structural Genomics ____________________
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Tumor Genetics _______________________________________________
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Biophysics of Macromolecules ___________________________________
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Molecular Genome Analysis ____________________________________
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Molecular Genetics ____________________________________________
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Pediatric Neurooncology _______________________________________
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Functional Genome Analysis ____________________________________
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Theoretical Bioinformatics ______________________________________
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Theoretical Systems Biology ____________________________________
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Signaling and Functional Genomics _____________________________
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Signal Transduction in Cancer and Metabolism ____________________
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Molecular RNA Biology and Cancer _______________________________
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Membrane Biophysics__________________________________________
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Systems Biology of Cell Death Mechanisms ________________________
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Proteostasis in Neurodegenerative Disease ________________________
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Lysosomal Systems Biology _____________________________________
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Cancer Risk Factors and Prevention ______________________
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Epigenomics and Cancer Risk Factors _____________________________
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Cancer Epidemiology __________________________________________
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Molecular Genetic Epidemiology ________________________________
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Biostatistics __________________________________________________
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Clinical Epidemiology and Aging Research _________________________
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Molecular Epidemiology ________________________________________
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Contents
Index ________________________________
142
Imprint ______________________________
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Translational Cancer Research __________________________
120
Translational Oncology _______________________________________
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Applied Tumor Biology ________________________________________
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Preventive Oncology __________________________________________
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Cellular and Molecular Pathology _______________________________
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Molecular Tumor Pathology ____________________________________
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Dermato-Oncology ___________________________________________
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Molecular Hematology/Oncology _______________________________
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Pediatric Oncology ___________________________________________
130
Molecular Oncology of Solid Tumors _____________________________
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Molecular Oncology of Gastrointestinal Tumors ___________________
132
Neurooncology ______________________________________________
134
Neuropathology _____________________________________________
135
Experimental Neuroimmunology _______________________________
136
Experimental Therapies for Hematologic Malignancies _____________
137
Molecular Mechanisms of Tumor Cell Invasion ____________________
138
Neuropeptides _______________________________________________
139
Infection and Cancer ____________________________________
108
Tumorvirology _______________________________________________
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Genome Modications and Carcinogenesis _______________________
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Viral Transformation Mechanisms ______________________________
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Characterization of Tumorviruses_______________________________
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Pathogenesis of Virus Associated Tumors_________________________
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Oncolytic Adenoviruses _______________________________________
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Noroviruses _________________________________________________
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Infection and Innate Immune Sensing Dynamics __________________
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Immunotherapy and Prevention ________________________________
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Imaging and Radiooncology _____________________________
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Radiology ____________________________________________________
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Medical Physics in Radiology ____________________________________
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Radiopharmaceutical Chemistry _________________________________
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Medical Physics in Radiation Oncology ____________________________
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Radiation Oncology ___________________________________________
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Molecular Radiooncology ______________________________________
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Nuclear Medicine ____________________________________________
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Medical and Biological Informatics ______________________________
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Optical Nanoscopy ___________________________________________
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Translational Radiation Oncology _______________________________
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Computer-assisted Interventions _______________________________
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Tumor Immunology ______________________________________
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Translational Immunology ______________________________________
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Immunogenetics ______________________________________________
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Molecular Immunology ________________________________________
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Developmental Immunology ____________________________________
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Cellular Immunology __________________________________________
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Innate Immunity ______________________________________________
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Immune Tolerance _____________________________________________
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The German Cancer Research Center (DKFZ) is
one of the worlds leading biomedical research
institutions. It serves the mission to identify
and study cancer risk factors and to unravel
mechanisms of cancer development. The
ndings from our basic research are systemati-
cally employed to develop new approaches for
prevention, diagnosis and treatment.
Employees: 2527
Staff Scientists: 774
Doctoral students: approx. 500
Scientists from 52 nations
(as of December 2012)
The German Federal Government provides
90 percent of the funding of the German
Cancer Research Center, and the State of
Baden-Wrttemberg the remaining 10 percent.
Additional income stems from external project
funding, license revenues, donations and
bequests.
The 46 scientic divisions, 26 junior research
groups and 10 clinical cooperation units are
assigned to seven Research Programs:
Cell Biology and Tumor Biology
Functional and Structural Genomics
Cancer Risk Factors and Prevention
Tumor Immunology
Imaging and Radiooncology
Infection and Cancer
Translational Cancer Research
DKFZ
The German Cancer
Research Center
Jointly with Heidelberg University Hospital,
DKFZ has established the National Center
for Tumor Diseases (NCT) Heidelberg where
promising approaches from cancer research
are translated into the clinic.
The Cancer Information Service (KID) provides
cancer patients, their families, and other
interested parties with information that is
readily understandable, scientically founded,
impartial, and up to date.
In 2011, the German Consortium for Trans-
lational Cancer Research was introduced to
the public by the BMBF, the German Federal
Government, as one of six German Centers
for Health Research. This initiative intends to
foster the nationwide strategic collaboration
of the most excellent scientists and clinicians
in exploring common cancer diseases.
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DKFZ Main Building
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DKFZ
The German Cancer
Research Center
TP4 Building
This building in the technology park of
the Neuenheim Campus was acquired in
2007 and provides additional space for
320 people.
7T MRI Building
As part of the strategic alliance with Sie-
mens, a 7T MRI system was installed in a
new facility. Thirty tons of steel included in
the surrounding walls shield the ultra high
magnetic eld from the environment.
TP3 Building
This building, completed in 2002, is where
genome research takes places. This so-
called Genome-Building harbors the
DKFZs sequencing facility with 15 high-
throughput next generation DNA sequenc-
ing instruments. It also houses servers
with a data storage capacity of 2 terabytes,
1.2 terabytes of which is reserved for the
three German projects in the International
Cancer Genome Consortium.
ATV Building
In the applied tumor virology building
scientists work with viruses that cause
cancer, such as HPV oder EBV, but also
with viruses that infect and kill cancer
cells, such as the oncolytic parvoviruses.
Research at DKFZ 2013
NCT
National Center for
Tumor Diseases Heidelberg
Initiated in 2004, and actively treating patients
since 2005, the National Center for Tumor Dis-
eases (NCT) Heidelberg was founded as an ex-
ceptional alliance between the German Cancer
Research Center (DKFZ), Heidelberg University
Medical School (HUMS) together with Heidel-
berg Medical Faculty and German Cancer Aid
(Deutsche Krebshilfe). NCT is a comprehensive
cancer center uniquely positioned to benet
from the wealth of DKFZ cancer research and
the Heidelberg biomedical campus. NCTs mis-
sion is two-fold: to provide optimal interdisci-
plinary oncology with current clinical therapies
and to rapidly transfer scientic knowledge
into clinical applications through comprehen-
sive translational and preventive oncology.
The new 5500 m
2
NCT Core Building has been
completed in 2010.
NCT is the principal portal of entry for all
oncology patients into the medical center, and
the primary location of all oncology outpatient
care. It integrates and supports all clinical and
translational research activities of DKFZ and
HUMS. DKFZs many scientic disciplines and
interactions, including strategic partnerships
with university medical centers and industry,
provide a strong framework for NCT projects.
In 2011, approx. 10,000 newly diagnosed cancer
patients were seen at NCT and more than
17,000 anti-tumor therapies were adminis-
tered. With more than 50,000 out-patient
visits p.a., patient numbers are steadily grow-
ing. 300 diagnostic, therapeutic and preventive
clinical trials, including investigator initiated
trials, were developed and conducted.
NCT pursues personalized oncology as a
center-wide master strategy that coordinates
all activities towards individualized cancer
medicine, including patient-oriented genetics,
proteomics, radiooncology, immunology and
prevention. The recently established Heidel-
berg Center for Personalized Oncology (DKFZ-
HIPO) forms a dedicated genomics, proteomics
and bioinformatics platform of DKFZ, enabling
excellent basic and translational research. Its
clinical counterpart, the NCT Precision Oncol-
ogy Program (NCT POP) combines molecular
diagnostics, innovative therapeutics develop-
ment, interdisciplinary patient care and pre-
vention to dene molecularly stratied patient
cohorts and hypothesis-driven treatments.
Towards this goal, the center aims to provide
comprehensive high-throughput genetic and
molecular analysis as a stratication tool for
every NCT patient by 2015.
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Cancer is a big challenge
Cancer disease is the second most frequent
cause of death in developed countries. Being
also an age-related disease, the number of
patients with cancer will increase as a conse-
quence of demographic changes.
Cancer is common: According to current g-
ures from the Robert Koch Institute, there were
more than 470,000 new cases of cancer in
2008; approximately half as many died from
cancer. Cancer is thus responsible for every
fth death in Germany.
Cancer treatment is becoming
increasingly individualized
Cancer research in the last two decades
has greatly increased our understanding of the
differing forms of cancer. Today we know much
more detail about the genetic changes which
cumulatively lead to malignant tumor disease.
Accordingly, changes in the treatment of some
cancer diseases have already been made. Pa-
thologists now analyze cancer tissue using
molecular biological methods and are able to
make resultant recommendations for treat-
ments with the highest response rates.
Cancer surgery and radiation therapies are
also becoming even more precise. Surgeons
are now better able to remove as much of
the tumor as possible, without damaging the
respective organs function. Likewise, radio-
therapists can apply the radiation therapy so
that the surrounding healthy tissue is spared
as far as possible.
Prevention and screening help to avoid cancer
Where a malignant tumor has already devel-
oped, it is often necessary to undertake elabo-
rate and costly treatment involving many dif-
ferent medical specialties. Of course, it would
be preferable for the cancer not
to reach that stage in the rst place. It is
actually possible, at least partly, to prevent
cancers occurring. Experts think every second
or third cancer diagnosis could be avoided by
prevention and targeted screening.
We in the German Consortium for
Translational Cancer Research are
taking on the challenge.
DKTK
The German Consortium for
At seven DKFZ partner sites the DKFZ
outstations closely cooperate with
prominent partners in university medi-
cine. At these joint translation centers
we pursue ambitious long-term pro-
grams in translational cancer research.
for treat-
ates.
pies are
FREIBURG
FRANKFURT/
MAINZ
ESSEN/
DSSELDORF
TBINGEN
HEIDELBERG
The DKTK partner locations
DKTK Berlin
Charit Comprehensive Cancer Center,
Medical University Berlin
PROFESSOR DR. REINHOLD SCHFER
DKTK Dresden
University Hospital Carl Gustav Carus TU Dresden,
Tumor Center Dresden, University Hospital Carl
Gustav Carus TU Dresden, Max Planck-Institute for
Molecular Cell Biology and Genetics, Helmholtz
Center Dresden-Rossendorf
PROFESSOR DR. MICHAEL BAUMANN
DKTK Essen/Dusseldorf
West German Cancer Center Essen University of
Essen, Heinrich Heine-University Dusseldorf
PROFESSOR DR. MARTIN SCHULER

DKTK Frankfurt/Mainz
University Center for Tumor Diseases Frankfurt,
Tumor Center Rhein-Main-Hospital, Goethe-
University Frankfurt, Georg Speyer-Haus Frankfurt,
Northwest Hospital Frankfurt, University Medical
Center of Johannes Gutenberg-University Mainz
PROFESSOR DR. HUBERT SERVE

DKTK Freiburg
Medical University at Albert-Ludwigs-University
Freiburg, Institute for Molecular Medicine and Cell
Research Freiburg University, Max Planck-Institut fr
Immunbiologie
PROFESSOR DR. CHRISTOPH PETERS

DKTK Heidelberg (Core Center)
German Cancer Research Center Heidelberg (DKFZ),
University Hospital Heidelberg, Medical Faculty
of Ruprecht-Karls-University Heidelberg, National
Center for Tumor Diseases Heidelberg (NCT),
Associated Partner: Paul Ehrlich-Institute Langen,
University Cologne
PROFESSOR DR. DR. H.C. OTMAR WIESTLER,
PROFESSOR DR. JOSEF PUCHTA

DKTK Munich
Ludwig-Maximilians University Munich,
Technical University Munich
PROFESSOR DR. WOLFGANG HIDDEMANN

DKTK Tbingen
Medical University at Eberhard-Karls-University
Tbingen, Comprehensive Cancer Center University
of Tbingen, Faculty of Life Sciences
of Eberhard-Karls-University Tbingen
PROFESSOR DR. KLAUS SCHULZE-OSTHOFF
The German Consortium for
Translational Cancer Research DKTK
Successful cancer research necessitates in-
tensive exchange between very differing
specialties. For this reason, cancer research
often takes place at very large centers; in the
USA in some incidences they have over 10,000
staff members. The German Consortium for
Translational Cancer Research reaches a critical
mass in another way, by establishing long term
links between the German Cancer Research
Center in Heidelberg and the largest university
hospitals in Germany. Currently, some twenty
institutions are cooperating at eight different
locations.
Seven programs in the ght against cancer
A core function of cancer research is the
continuous review of fundamental research
results to identify new targets for prevention,
diagnosis and treatment of cancer diseases.
Over 160 physicians, scientists and their groups
in the DKTK are committed to this transla-
tional concept.
There are seven dened research programs,
in each of which an increasing number of
sites will participate:
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Signaling Pathways in Carcinogenesis
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Molecular Diagnostics
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Cancer Immunology and Immunotherapy
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Stem Cells
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Radiation Therapy and Imaging
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Therapy Resistance
|
Prevention and Screening
Joint platforms harness strengths
The joint research work within DKTK is vitally
supported by ve platforms providing the
necessary infrastructure for the Consortium.
A core element is the Clinical Communica-
tion platform. It allows for the recruitment of
patients at all sites and also serves as a shared
pivot in innovative clinical trials. In addition,
there will be technically oriented platforms.
The aim is to harmonize the technical require-
ments over all sites to ensure comparable data
and to provide a common structure allowing
scientists from all locations access to methods
that would otherwise be unavailable.
Attractive offers for junior researchers
In cancer research it is essential that differ-
ent disciplines pull together. Accordingly, a
broad program to develop junior researchers is
extremely important. Young medical doctors,
especially those with some clinical experience
are to be offered the opportunity of training
in cancer research at the School of Oncology.
Likewise, researchers with a background in nat-
ural sciences will be introduced to translational
research. A grant program is one of the meas-
ures being developed to further these aims.
The individual research platforms are
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Clinical Communication
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Service Units
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Preclinical Models
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Active Pharmaceutical Ingredient
Development
|
School of Oncology
Research at DKFZ 2013 11
BERLIN
DRESDEN
MNCHEN
12
The idea was revolutionary back in 1972.
Flying in the face of prevailing expert
opinion, Harald zur Hausen hypothesized
that the viruses that cause warts might
also play a role in the development of
cervical cancer.
Supplying the evidence turned out to be
more difcult than he had anticipated. In
1983, however, after years of relentless
searching, zur Hausen and his team
at last succeeded in isolating the DNA
of this pathogen, also known as human
papillomavirus (HPV), in a biopsy. What
they had found was HPV16, a hitherto
unknown representative of the large and
complex family of papillomaviruses. In
the following years, it transpired that
the two high-risk virus types HPV16
and HPV18 are responsible for around
70 percent of all cases of cervical cancer
worldwide. A total of 15 of the 170 HPVs
so far identied have been shown to be carci-
nogenic. The DNA of papillomaviruses is found
inmore than 99 percent of all tissue samples
taken from women with cervical cancer.
This type of cancer affects around half a
million women every year. The disease
often ends in death, especially in Third
World countries which cannot afford cancer
screening programs.
Following their discovery of carcinogenic
papillomaviruses, zur Hausen and his
team studied how the pathogens survive
in the cell and how the cells eventually
mutate into cancer. It was their understan-
ding of the biology of infection that
enabled them to develop a vaccine to
protect women against cervical cancer.
Harald zur Hausen served as Chairman of the
German Cancer Research Center from
1983 to 2003. In 2008, he was awarded the
Nobel Prize in Medicine in honor of his
outstanding contribution to science.
Press conference on October 6, 2008 in the DKFZ Communication Center.
Nobel Prize
in Medicine
2008
Harald zur Hausen

The Life Science Lab which has been estab-
lished at DKFZ offers extracurricular oppor-
tunities to talented middle and senior high
school students with a particular interest in
math and science. Here, the focus is on those
areas in the life sciences in which research is
being conducted at DKFZ and partner institu-
tions.
In addition to helping the students to develop
interdisciplinary competence and to achieve
personal goals that are educationally sig-
nicant, they are also encouraged to work
independently and to take responsibility for
research activities so as to experience the
pleasure of discovery and to learn how to col-
laborate constructively.
The multi-year program is organized into six
areas of activities:
1. Public Friday lectures on scientic, theo-
retical, and philosophical topics aim to
awaken curiosity in the students.
2. Core research work takes place in
scientist-mentored work groups in the
elds of archeology, astrophysics, chem-
istry, experimental physics, informatics,
climatology, art, mathematics, molecular
cell biology, neuropsychology, medicine,
pharmacy, philosophy, political science,
quantum physics, robotics, synthetic biol-
ogy, systems biology, theoretical physics,
commerce, and zoology.
3. Weekend seminars present opportuni-
ties to broaden the scope of work group
research.
4. (Inter)National summer academies, for
example, internships lasting for several
weeks as research fellows at various dif-
ferent universities, afford opportunities
to put the acquired competence into an
international context.
5. The Bio-Science Lab and Phys-Tech Lab
give depth to the broad theoretical
instruction in the areas of biochemistry,
molecular and cell biology, as well as in
physics and technology, through both
mentor-initiated and independent practi-
cal laboratory work.
6. Research projects performed under
scientic guidance promote the success-
ful development of ideas or separate
subprojects and facilitate self-organized
and exploratory learning.
Successful applicants may participate from
eighth grade through to high school gradua-
tion. Students in their nal year of school share
their experience by acting as student mentors.
Since 2005, the Alumni Association has been
bringing former participants together, which
furthers networking.
Of particular signicance is the integration
into genuine research through the participa-
tion of scientic mentors from DKFZ, EMBL,
the universities of Heidelberg, Mannheim,
Kaiserslautern, and Landau as well as from
Max Planck Institute, Heidelberg. The Life Sci-
ence Lab is further supported by cooperation
partners from business and public sectors.
In 2009, the Life Science Lab won First Prize
in the competition School meets Science
sponsored by the Robert-Bosch Foundation for
its model character, while in 2010 the Initia-
tive Germany Land of Ideas awarded the
Lab the status Designated Site of Ideas. In
2012 the team of the Life-Science Lab won the
Grand Prize (GreenBrick Trophy) at the IGEM
HighSchool Jamboree of the MIT as well as 5
out of the 10 Special Prizes: Best New BioBrick
Part, Natural; Best New BioBrick Part or Device,
Engineered; Best Experimental Measurement;
Best Wiki; Best Presentation.
Dr. Katrin Platzer
Life-Science Lab
DKFZ
Im Neuenheimer Feld 581
69120 Heidelberg
Tel.: (+49)6221/4214-01
Fax: (+49)6221/4214-10
Email: k.platzer@dkfz.de
www.life-science-lab.org
Participants in the robotics seminar construct a
robot together with doctoral candidates from
Kaiserslautern University (picture above).
High school students work to obtain their Lab
License at the Bio-Science Lab (picture in the
middle).
Good attendance at one of the weekly Friday lectu-
res (picture below).
DKFZ Life-Science Lab:
A place where students can think and experiment
Research at DKFZ 2013
The Helmholtz International Graduate School
for Cancer Research is the PhD Program of the
German Cancer Research Center. The Graduate
School has approximately 500 members, from
all divisions and research groups of the center.
Through the Graduate School, PhD students
receive world-class training in interdisciplinary
cancer research in preparation for a successful
career in science.
Members are recruited bi-annually from
around the world through a highly competi-
tive and stringent selection procedure. A core
feature of the Graduate School is committed
to scientic supervision of graduate students
through annual Thesis Advisory Committees
(TACs), consisting of the students PhD supervi-
sor and at least two other senior scientists,
one of whom is external to the German Cancer
Research Center. The TAC meetings moni-
tor the students progress, offer feedback on
research already conducted and discuss any
other issues, which might be relevant to the
students work.
Graduate students are further supported
through a comprehensive training program,
starting with a one-week initial course dur-
ing the rst months of their PhD and further
professional training throughout their PhD
through scientic and soft-skills courses,
lecture series and careers seminars. Each stu-
dent also takes part in the graduate student-
organized PhD retreat in their second year,
including, in addition to a scientic program,
career talks external speakers and talks from
student guests of international collaborating
institutes. The program of the Graduate School
therefore ensures that throughout the PhD,
scientic supervision, networking and coopera-
tion between graduate students and leading
scientists is facilitated at an international level.
A further branch of graduate education, the
German-Israeli Helmholtz Research School
in Cancer Biology was established in 2012 in
collaboration with the Weizmann Institute
of Science in Rehovot, Israel. Research School
graduate students work on joint scientic
projects and are jointly supervised by a senior
scientist from both the German Cancer
Research Center and the Weizmann Institute.
All projects include an extended research stay
at the partner institute, during which time
the graduate students have full access to the
resources and services of the partner through
integration into the respective graduate
schools. Annual meetings, joint workshops and
on-going seminar series and courses of the
Research School ensure a continuous exchange
between the partners.
If you are interested in nding out more about
the opportunities for graduate studies at the
German Cancer Research Center, then please
visit our website: www.dkfz.de/phd
Manager of the Graduate and Research
Schools: Dr. Lindsay Murrells
Contact: higs@dkfz.de
Graduate Studies at the DKFZ
Helmholtz International Graduate School
for Cancer Research

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Cancer Information Service
National Reference Center for Cancer Inform ation
The Cancer Information Service was estab-
lished at the German Cancer Research Center
in 1986. The aim was to offer up-to-date, qual-
ity assured information in all areas of cancer
for cancer patients, their families and friends,
and for the interested public. Additionally,
the service reaches out to health profession-
als involved in the care and support of cancer
patients.
The information provided by the Cancer Infor-
mation Service is independent and compre-
hensive. It is evidence-based, readily under-
standable and tailored to individual needs.
The Cancer Information Service answers indi-
vidual questions on all cancer-related topics:
causes and risk factors, prevention, diagnosis,
treatment and follow-up care. In addition, the
Cancer Information Service supplies contact
details of institutions and organizations
involved in medical and psychosocial care and
support of cancer patients.
The information is provided via telephone,
e-mail and its most informative up-to date
homepage www.krebsinformationsdienst.de.
The service also issues various brochures and
continuously updated fact sheets on relevant
topics.
At the National Center for Tumor Diseases
(NCT) Heidelberg and at the University Cancer
Center (UCC) Dresden, the Cancer Information
Service offers face-to-face counseling.
The telephone service is available daily from 8
a.m. to 8 p.m. at 0 800 420 30 40. Calls within
Germany are toll-free. If all lines are busy, call-
ers can leave a callback request.
All e-mail inquiries to krebsinformationsdi-
enst@dkfz.de or via the secured e-mail form
on the Cancer Information Service website are
being answered within two workdays.
On its website www.krebsinformationsdienst.de,
the Cancer Information Service provides
information on a multitude of topics, such as:
new research ndings, up-to-date scientic
knowledge in oncology, useful tips for cancer
patients, contact information, and links to fur-
ther quality assured information resources.
The Staff
Physicians who have received special training
in health communication answer telephone
and e-mail inquiries. Science journalists and
scientic staff from the areas of medicine,
pharmacy, biosciences and psychology are re-
sponsible for literature and information review
and editing.
Prospects National Reference Center for
Cancer Information
The high demand for quality assured cancer
information will continue to grow due to
demographic trends. In order to provide access
throughout Germany, the Cancer Information
Service strengthens its team and expands
its services. The strong integration into the
German Cancer Research Center as well as its
commitment to quality assurance in cancer
information are prerequisites for its expansion
to a national reference center for cancer infor-
mation by the Federal Ministry of Education
and Research (BMBF).
The Cancer Information Service
Performance Figures 2011
Inquiries answered 32.724
Telephone service 26.758
E-mail service 5.325
Letters 489
Face-to-face counseling 146
Website accessed 74.038.328
Cancer Information Service
Head of Department:
Dr. Susanne Weg-Remers
Cancer we answer your questions
Phone 0 800-420 30 40
Daily from 8 a.m. to 8 p.m.
Toll-free within Germany
krebsinformationsdienst@dkfz.de
www.krebsinformationsdienst.de
In 2002, the Unit Cancer Prevention was
nominated as a World Health Organization
Collaborating Centre (WHO-CC) for Tobacco
Control, with the objective of making a notice-
able contribution to national and international
efforts to curb tobacco consumption. Its three
main aims are to prevent the onset of smok-
ing, to help smokers to quit, and to protect the
population against secondhand smoke.
Since the establishment of the WHO-CC,
several measurable results have been achieved.
Legislation for the protection of non-smokers
from secondhand smoke was introduced; one
Federal Law and 16 State Laws in 2007/2008
are based on the Centres scientic ground-
work.
Several other national tobacco control policies
have been implemented, for which the WHO-
CC for Tobacco Control developed recommen-
dations.
Furthermore, the WHO-CC for Tobacco Control
elaborated guidelines for implementation of
Article 12 (education, communication, training
and public awareness) of the WHO Framework
Convention on Tobacco Control (WHO-FCTC).
In order to increase the evidence base for
tobacco control policies, the WHO-CC col-
laborates with the International Tobacco
Control (ITC) Policy Evaluation Project. As an
ongoing cohort study, the ITC project follows
smokers and non-smokers for several years
and can thus monitor the effects of tobacco
control measures on individual attitudes and
behaviour.
Signicant accomplishments of the past years:
The WHO-CC:
demonstrated that in 2007, 106,623
deaths were attributable to cigarette
smoking in Germany and that there
was a north-south gradient regard-
ing the tobacco-attributable mortal-
ity rate (Gesundheitswesen 2010,
doi:10.1055/s-0030-1252039).
showed that numerous tobacco addi-
tives are increasing the attractiveness
Unit Cancer Prevention
WHO Collaborating Centre for Tobacco Control
and palatability of cigarettes as well as
the health risks of smoking (SCENIHR.
Addictiveness and attractiveness of Tobacco
Additives. 12 November 2010, http://
ec.europa.eu/health/scientic_com-
mittees/emerging/docs/scenihr_o_031.
pdf; Public Information Tobacco Control
(PITOC), http://www.dkfz.de/de/tabak-
kontrolle/PITOC_Additives_in_Tobacco_
Products.html).
published data on menthol capsules in
cigarette lters showing that they are at-
tractive to young people, thus promoting
smoking initiation. Based on this scientic
evidence a German court prohibited the
introduction of cigarettes with menthol
capsules on the German market (German
Cancer Research Center (Ed.), Menthol
Capsules in Cigarette Filters - Increasing
the Attractiveness of a Harmful Product,
Heidelberg, Germany, 2012; Verwal-
tungsgericht Braunschweig (2012) Urteil
Az. 5 A 206/11).
showed that public smoking bans pro-
mote smoking reduction at home (Mons
U, (2012): Frdern ffentliche Rauchver-
bote auch ein rauchfreies Zuhause? Sucht
Magazin 38 (3&4): 21-22).
disclosed the German Cigarette Industry
Organizations role in obstructing the de-
velopment and implementation of effec-
tive tobacco control policies in Germany
(Gesundheitswesen 2008, 70:315-24).
published the rst National Tobacco Atlas
Germany 2009, an illustrative education
handbook on the social, health and eco-
nomic aspects related to tobacco and its
use (Tabakatlas Deutschland 2009, 2009,
Steinkopff Verlag).
published German language text and
comments, in collaboration with the
German Ministry of Health, on the
WHO Framework Convention of Tobacco
Control and recommendations for Ger-
many (Perspektiven fr Deutschland: Das
Rahmenbereinkommen der WHO zur
Eindmmung des Tabakgebrauchs - FCTC,
2011, DKFZ).
German Cancer Research Center
Unit Cancer Prevention
WHO Collaborating Centre for Tobacco Control
Head of Department:
Dr. Martina Ptschke-Langer
D-69120 Heidelberg
Tel.: 06221-423008
Fax : 06221-423020
E-Mail: who-cc@dkfz.de
18
Heidelberg
A Capital of Biomedical Sciences
in Europe
University of Heidelberg
Heidelberg University, founded in 1386, is Ger-
manys oldest university and has one of the
strongest research proles in Europe.
The successes in the Excellence Initiative and
in international rankings prove its leading role
in the scientic community. In terms of educat-
ing students and promoting promising young
academics, Heidelberg relies on research-based
teaching and a well-structured training for
doctoral candidates.
Heidelberg University is a comprehensive
university with the full spectrum of subjects
including medicine. It aims to strengthen the
individual disciplines, to further interdiscipli-
nary cooperation and to make research results
usable for society and industry. Heidelberg also
draws its strength from its cooperation with
local non-university research institutions such
as the DKFZ and the Max Planck Institutes. In
addition, the university is tied into a worldwide
network of research and teaching collabora-
tions which give evidence of its marked global
interconnectedness.
In the charming city of Heidelberg with
its biomedical Campus Neuenheim
DKFZ is surrounded by strong partner
institutions.
Heidelberg University Hospital
and Medical Faculty
Heidelberg University Hospital is one of the
largest and most prestigious medical centers
in Germany. The Medical Faculty of Heidelberg
University belongs to the internationally most
renowned biomedical research institutions in
Europe. Both institutions have the common
goal of developing new therapies and imple-
menting them rapidly for patients. With about
11,000 employees, training and qualication is
an important issue. Every year, around 550,000
patients are treated on an inpatient or outpa-
tient basis in more than 50 clinics and depart-
ments with 2,000 beds. Currently, about 3,600
future physicians are studying in Heidelberg;
the reform Heidelberg Curriculum Medicinale
(HeiCuMed) is one of the top medical training
programs in Germany.
European Molecular Biology
Laboratory Heidelberg
The European Molecular Biology Laboratory
is a basic research institute funded by public
research monies from 20 member states and
associate member state Australia. Research
at EMBL is conducted by approximately 85
independent groups covering the spectrum
of molecular biology. The Laboratory has ve
units: the main Laboratory in Heidelberg, and
Outstations in Hinxton (the European Bioin-
formatics Institute), Grenoble, Hamburg, and
Monterotondo near Rome. The
cornerstones of EMBLs mission are: to perform
basic research in molecular biology;
to train scientists, students and visitors at
all levels; to offer vital services to scientists
in the member states; to develop new instru-
ments and methods in the life sciences and
to actively engage in technology transfer
activities. Around 190 students are enrolled
in EMBLs International PhD programme. Ad-
ditionally, the Laboratory offers a platform
for dialogue with the general public through
various science communication activities such
as lecture series, visitor programmes and the
dissemination of scientic achievements.
Max Planck Institute for
Medical Research Heidelberg
The institute was opened in 1930 as the Kaiser
Wilhelm Institute for Medical Research, and
was re-founded as a Max Planck Institute in
1948. Its original goal was to apply the meth-
ods of physics and chemistry to basic medical
research, and it still works on fundamental bio-
logical questions that are of long-term medi-
cal signicance. One main area of research is
neurophysiology: What are the changes in the
brain that underlie processes like learning and
remembering? What does the three-dimen-
sional circuit diagram of the billions of nerve
cells in the brain look like? How can the pro-
cesses in nerve cells in the living brain be made
visible through new microscopic methods? The
scientists also try to understand how percep-
tions of odours are stored in the brain, and
how networks are formed which are capable
of adapting to stress. A second main area of
research at the Institute concerns the complex
chemical reactions in living cells. These are per-
formed by enzymes, and the research aims to
determine the atomic structure of important
enzyme molecules.
Research at DKFZ 2013/2014 19
Core Facilities
20
CORE
FACILITIES
The DKFZ Core Facilities provide the infrastructure for
excellence. Cutting-edge techniques and equipment are
the foundation of high quality research.
At each core unit, experienced scientic and techni-
cal staff members assist researchers in the planning,
conduct and analysis of experiments. These services are
available to all DKFZ members and visiting scientists.
Genomics and Proteomics
Biomedical research increasingly depends on
global molecular analyses of normal and dis-
eased phenotypes. These include qualitative as
well as quantitative investigations at the ge-
nome and proteome levels, that are required to
eventually achieve a mechanistic understand-
ing of disease or to identify novel markers
for diagnosis, prognosis or prediction. Central
infrastructures are key components in such
research processes, as these provide access to
state-of-the-art technology platforms that are
operated by dedicated personnel, thus over-
coming redundant implementation of often
demanding technologies within an institute.
Along these lines, the Genomics and Proteom-
ics Core Facility (GPCF) of the DKFZ covers four
major areas and provides professional services.
The genomics part of the facility operates
one of Europes largest next-generation
sequencing units. We sequence within
several national and international cancer
genome projects, in addition to a vari-
Head
PD DR. STEFAN WIEMANN
Units
High-Throughput Sequencing
Microarray,
Bioinformatics (HUSAR)
Monoclonal Antibodies
Protein Analysis
Protein Interaction Screening
Molecular Structural Analysis
ety of individual in-house projects. Gene
expression proling, genotyping and
methylation analysis is carried out using
array-based technologies, providing high
throughput at reasonable cost. All these
applications generate molecular proles
at the level of nucleic acids and provide
information about alterations in the dis-
ease context.
Technologies in mass spectrometry and
NMR are provided for qualitative and
quantitative analysis of proteins, protein
modications and small molecules. These
applications allow views of the activa-
tion states of signaling proteins in cancer
pathways and help to generate mecha-
nistic knowledge of tumor diseases. We
further provide small and large-scale
technologies to analyze interactions of
proteins with other molecules.
In the eld of functional genomics, we-
generate monoclonal antibodies target-
ing cancer-relevant proteins, some of
Core Facilities
Next Generation Sequencing
which are now used in diagnosis. The au-
thentication and contamination control
of cell lines is offered as an essential part
of quality control within in vitro studies.
Cell lines stably expressing recombinant
proteins from isogenic loci in the respec-
tive genomes are generated to assess
phenotypes of proteins and mutants in
in vitro as well as in vivo systems, e.g.,
xenograft mouse models (collaboration
with animal facility).
The central infrastructure of the GPCF of-
fers assisted access to costly instruments,
and distributes the human ORF clone
resource of the international ORFeome
Collaboration for recombinant expression
of encoded proteins, e.g., in isogenic cell
lines.
Our mission is to always enable application
of state-of-the-art technologies. We carry out
joint projects with scientic groups within
DKFZ to implement the latest technologies
that serve the needs of science. In addition to
providing full or assisted access to services, we
are involved in the DKFZ teaching program,
and organize tech-talks, seminars and practical
courses where we inform interested scientists,
predocs and technicians on the technological
background of applications.
22
Imaging and Cytometry
Head
PROF. JRGEN KARTENBECK (IN CH.)
Units
Light Microscopy Facility
Core Facility Electron Microscopy
Small Animal Imaging
Flow Cytometry
Biomedical research benets greatly from
imaging and cell enrichment processes, but
scientic results in these elds are reliant upon
the efcient and correct use of complex and
expensive instrumentation. Dynamic progress
in the development of such technology results
in a constant requirement for new or updated
equipment, as well as experienced staff mem-
bers able to guarantee the correct, appropriate
use of the instruments; execution of the exper-
iments; and data management all of which is
time consuming.
In order to minimize such investment of capi-
tal and personnel for individual groups, the
DKFZ has established the Imaging and Cytom-
etry Core Facility; made up of individual units,
it provides a wide range of high quality servic-
es in four different elds for all DKFZ members
and visiting researchers.
Each unit is directed by a highly experienced
scientist. The units are responsible not only
for the allocation and maintenance of instru-
ments, lab space and to some extent, consum-
ables, but their scientic and technical staff
also offers training and assistance in sample
preparation, instrument application, experi-
mental set-up design, interpretation of the re-
sults, and detailed, unit-specic seminars.
Core Facilities
Small Animal Imaging Flow Cytometry Light Microscopy Electron Microscopy
1. The Light Microscopy unit provides a
number of manual and fully automated
wide-eld and confocal laser-scanning
microscopes. The range of services is sup-
plemented by support in sample prepa-
ration (e.g. parafn and cryo-sectioning,
laser microdissection) and spatial visu-
alization of whole-mount specimens, as
well as data analysis and digital image
processing.
2. The Electron Microscopy (EM) unit of-
fers full service and guided access in EM
preparation and imaging, including con-
ventional Epon-EM, low-temperature EM
(high-pressure freezing, freeze substitu-
tion and cryo-sectioning), immuno-EM
and single particle EM (negative staining,
rotary shadowing).
3. The Small Animal Imaging unit supports
clients with a variety of radiological meth-
ods, among them ultrasound, PET, CT,
SPECT and MRT, to collect and quantify
morphological and functional data in vivo.
4. The Flow Cytometry unit performs cell
cloning or enrichment of up to 4 subpop-
ulations simultaneously by using several
ow cytometric cell sorters (up to 5 laser,
cuvette and jet-in-air sorter), enabling
analysis of up to 19 parameters per cell.
Information Technology
At the DKFZ, both the need for Information
Technology (IT) and its use have increased
greatly over recent years. This is due to several
inuencing factors: Firstly, our everyday work
relies increasingly on IT, such as communica-
tion technology and ofce applications and,
second, the needs of science are continuously
changing and evolving. Examples include mat-
ters of mobility and communication, interna-
tional collaborations, bioinformatics projects
with high demands on data transmission and
data storage capacities, processing of data
from laboratory instruments such as micro-
scopes and cell sorters or from large medical
systems, professional presentation of scientic
results and others.
The task of the Information Technology Core
Facility is to ensure optimal use of information Head
HOLGER HAAS
Working Groups
Applications
Web Application Development
Desktop Services
Central Servers
Networks
technology at the DKFZ, to advise staff from all
departments in selecting IT tools for their spe-
cic needs in a general context, to implement
and operate central IT services and to support
individual solutions in planning and operation.
This is done on a service-oriented basis. Since
all essential strategic and operative functions
and tasks at the DKFZ are substantially sup-
ported by IT, there are high demands on the
availability and security of IT systems.
The working group Software Systems pro-
vides software on server systems and applica-
tions for client systems. This includes central
services like user account management,
software distribution and licence manage-
ment, access- and resource management for
le services , maintenance and administration
Core Facilities
for ms-sql server, webserver and several other
software platforms.
The working group Databases" is responsible
for providing database development and sup-
port. Furthermore a technical support of the
DKFZs internet and intranet services takes
place.
The working group Desktop Services runs the
service center for user enquiries and works on
matters relating to the desktop environment
such as notebooks, Windows and MacOS, and
operates the high-quality printing center.
Central servers, printing services, data storage
and scientic computing are the responsibili-
ties of the working group Central Servers.
The working group Networks takes care of
the physical data network and security ser-
vices.
24
Core Facilities
Animal Laboratory Services
Cancer represents a devastating disease. The
mission of the DKFZ is research on the mo-
lecular mechanisms of carcinogenesis and the
improvement and development of cancer ther-
apies. Scientists at the DKFZ work, whenever
possible, with cell cultures or try to answer
scientic questions by computer simulation
(replacement). In many cases, due to the com-
plexity of tumorigenesis the signicance of al-
ternative in vitro or in silico systems is limited,
so that animal experiments are indispensable.
These are restricted to the minimum extent
possible (reduction); animals are treated with
respect and with the most advanced tech-
niques (renement). For their experiments,
DKFZ scientists preferentially use rodents, in
rare cases, amphibians also. To mimic the de-
velopment of a distinct cancer in humans, can-
cer researchers employ various tumor models;
genetically manipulated mice with a tissue-
specic gain or loss of one or several genes
serve to evaluate the functional role of such
genetic factors in cancer development.
To some extent, the mechanisms of tumor
development are analysed in mice that have
been treated with carcinogenic agents. To
study the characteristics of human tumor cells,
mice with a compromised immune system are
Head
PD Dr. Kurt Reifenberg
Units
Tumor Models Service
Cryopreservation Service
Animal Laboratory Facility
Microbiological Diagnostic and
Laboratory Animal Medicine
Transgenic Service
often used, since they tolerate the transplanta-
tion of cells from other species and allow their
growth.
The staff of the DKFZ Animal Laboratory Ser-
vices Core Facility supports scientists requiring
animal organs or animals, bred in-house or
selectively purchased, for experimentation. A
team of clinical veterinarians and biologists
advises and assists researchers in the design
and realization of their experiments. Managers
of the core facility train technicians and care-
takers and provide technical courses for scien-
tic personnel. By these means, it is assured
that all animals are kept according to national
and international animal welfare laws. In ad-
dition, the welfare of the animals is ensured
by maintaining them under the most hygienic
conditions.
In the Laboratory of Microbiological Diagnos-
tics and Animal Medicine, the health status of
the animals is regularly checked (www.dkfz.
de/en/abteilungen/v/v231.html). The Trans-
genic Service supports scientists at DKFZ in
the generation of genetically modied mouse
lines that serve for investigation of distinct
human tumor diseases (www.dkfz.de/en/
transgen-service/index.html).In the Cryopreser-
vation Unit, the most important mouse strains
are preserved for further studies by collecting
spermatozoa or early-stage embryos from mu-
tant mice and subsequent freezing in liquid
nitrogen. In addition, a database of all mouse
mutants available in-house is provided (www.
dkfz.de/en/kryokonservierung/index.html).
The Tumor Models Unit carries out cancer
studies in experimental animals by application
of carcinogenic agents and by transplantation
of tumor cells into immune-decient mice. Ad-
ditionally, diet and therapy studies are carried
out (www.dkfz.de/en/tumormodelle/index/
html).
Core Facilities
Library
Head
DAGMAR SITEK
Due to technical development, research
and scientic communication processes are
currently facing large changes. Today, the
ood of information is rising rapidly. If this
information is used wisely in conjunction
with ever-increasing projects, tools and
programs, it will become a valuable addition
to researchers. Here, the library is supporting
the scientists in all aspects of scientic
information and communication.
The librarys team obtains the required
scientic literature and information which is,
amongst others, provided through the librarys
website. Currently, the library offers access
to more than 1000 e-journals. Monographs,
reference books, laboratory handbooks etc. are
available online, as well as in print. Publica-
tions that are not available from the librarys
collection may be ordered through document
delivery and thus made available.
Several databases are offered by the library
for literature searches. Here, the library offers
individually customized trainings in databases
like PubMed, Web of Science and SciFinder.
The same is true for the bibliographic ma-
nagement software EndNote and Reference
Manager.
The librarys reading room offers a quiet
working space with wireless internet and the
possibility of immediate help from the staff if
needed.
We also offer assistance when questions invol-
ving bibliometric issues, citation analysis, open
access or copyright arise.
The library is also responsible for the DKFZ
publications database. Currently, the library is
working with scientists in order to expand the
database to an institutional repository.
Furthermore, the library is parenting the DKFZ
archive. This archive collects and registers all
documents regarding the history of the DKFZ.
The librarys reading room
26
Core Facilities
Joint Chemical Biology Core Facility of EMBL & DKFZ
Small inhibitory molecules are widely used as
therapeutic agents, but they are also excel-
lent bio-tool compounds for basic research.
They are often used as experimental tools to
address important biological questions via
loss-of-function experiments. The aim of this
core facility is to provide research groups with
inhibitory molecules against their target of
interest and enable them to answer essential
questions in their research. The facility assists
groups in the development of primary and
secondary assays for screening against our
in-house compound library and guides them
through the process of identifying bio-tool
compounds for their specic target. It also of-
fers computational chemistry services.

The Chemical Biology Core Facility is a collabo-
ration between DKFZ, the European Molecular
Biology Laboratory (EMBL) in Heidelberg and
Heidelberg University, and is located at EMBL.
For further information on this service, please
visit the site: www.embl.de/services/core_fa-
cilities/chemcore/index.html
Medicinal chemistry support is usually
required following a small molecule screen.
Here, the research group Cancer Drug De-
velopment headed by Dr. Aubry Miller offers
assistance on a collaborative basis.
Head
DR. JOE LEWIS
In cooperation with
EMBL
University of Heidelberg
Ligand docked into target protein
Research Programs 28
RESEARCH
PROGRAMS
The DKFZ covers the entire breadth of modern cancer research.
Fields of research range from knowledge of the molecular basis of
the development of cancer, distribution and risk factors within the
population to diagnosis and treatment.
More than 100 division heads, group leaders and senior scientists,
200 Postdocs and about 500 PhD students work together at the
DKFZ. As an interdisciplinary environment, DKFZ employs scientists
with qualications in medicine, biology, biochemistry, physics, che-
mistry, mathematics , informatics or related issues.
At DKFZ, researchers benet from intensive scientic exchange
between research programs and individual groups which serves as
a basis for the internationally renowned research at the center.
Research groups are organized in seven research programs: Cell
Biology and Tumor Biology, Functional and Structural Genomics,
Cancer Risk Factors and Prevention, Tumor Immunology, Imaging
and Radiooncology, Infection and Cancer, and Translational Cancer
Research.
Cell Biology and
Tumor Biology
Research Program (FSP-A) concentrates the basic cell and tumor biology-focused research
groups at the center. As such, the mission of the FSP-A groups is either the molecular,
cellular and functional analysis of the mechanisms leading to tumor initiation, tumor
promotion and tumor progression including metastasis or the pursuit of fundamental
discipline-independent basic science. Scientists of the research program Cell and Tumor
Biology aim at tackling these fundamental questions:
They investigate how genome stability is ensured, as inherited or acquired alterations
in the genome are causative for tumor initiation and progression. The experimental
program also focuses on epigenetic mechanisms and RNA biology.
They study cell surveillance and damage control mechanisms, which allow cells to
monitor molecular processes and respond to pathologic damage. This includes the
control of protein stability and turnover.
They unravel critical signaling pathways and networks which enable cells to perceive
and correctly respond to information and to govern cellular processes. Scientists in
this research program investigate how dysregulation of these mechanisms is linked to
malignancies.
They analyze cell differentiation pathways and the biology of stem and progenitor
cells taking into consideration that perturbed cell differentiation and dysregulated
stem cell programs are at the heart of many oncological and non-oncological diseases
They exploit the complexity of tumor cell interactions with their microenvironment to
analyze a tumor not just as a clump of tumor cells leading to local disease but rather
as a complex pathologic organ causing systemic disease. Metabolic changes are stu-
died as risk factor and consequence of tumorigenesis and tumor progression.
To tackle these questions, the scientists employ a broad array of highly specialized mole-
cular, cellular and organismic tools and techniques. With scientic excellence being the
primary recruitment criterion, outstanding groups are afliated with the FSP-A. Thus, their
cutting-edge basic cell and tumor biology research establishes the knowledge-based
foundation for the rational translation and exploitation into medical application for some
of the most devastating human diseases. For a conceptually broader basic science appre-
ciation beyond its primary tumor biology focus, DKFZs cell and tumor biology research
program is part of the DKFZ-ZMBH-Alliance, a strategic partnership between the FSP-A and
the Center for Molecular Biology of Heidelberg University (ZMBH) which was established
in 2007 in order to overcome the classical boundaries between the two strong university
and non-university institutions on the Heidelberg campus. Details about research projects
of the individual FSP-A research groups can be found on the respective pages.
Coordinator
PROF. DR. HELLMUT AUGUSTIN
Research Program 30
Research Program 32
Cell and Tumor Biology
Stem cells are essential to maintain regenera-
tive tissues, and are a critical component of
repair processes in response to tissue injury
and infection. Moreover, genetic alterations of
stem cells and their progeny can lead to the
generation of cancer stem cells (CSCs) that can
drive tumorigenesis in hierarchically organized
cancer entities. Due to their remarkable resist-
ance to chemotherapy and radiation, CSCs are
thought to be responsible not only for tumor
re-occurrence but also for initiation and main-
tenance of metastases. One of the goals of the
Division of Stem Cells and Cancers research
program is to elucidate the molecular and cel-
lular basis of hematopoietic stem cell (HSC)
self-renewal and differentiation as well as to
characterize the complex dynamic interactions
within the stem cell-niche unit. In addition,
the group has established a program to func-
tionally characterize malignant stem cells of
leukemias and carcinomas at various levels. For
example, circulating metastasis initiating cells
have been isolated from the blood of breast
cancer patients. They are quantied and func-
tionally characterized in orthotopic transplan-
Head: Prof. Dr. Andreas Trumpp
tation models. Their capacity to seed distant
metastases is linked to cell surface receptors
and the activity of certain signaling pathways.
In addition, we have identied novel subclass-
es of pancreatic cancer, which show striking
differences in their response to conventional
and targeted therapies. Genomic and molecu-
lar characterization of subtype specic cancer
and metastasis stem cells will provide the ba-
sis for the generation of novel diagnostic and
therapeutic tools to target advanced chemo-
resistant cancers including metastasis.
Future Outlook:
The program characterizes both normal and
malignant stem cells by in vivo approaches. We
use genomic, genetic, molecular and cellular
methods to uncover the mechanism of normal
and uncontrolled self-renewal. Starting with
model systems, we typically extend our work
to the analysis of primary patient derived sam-
ples with the goal to develop innovative strate-
gies to detect and target cancer and metasta-
sis stem cells in clinical settings.
ESSENTIAL PUBLICATIONS: (1.) Wilson A. et al. (2008).
Hematopoietic stem cells reversibly switch from dor-
mancy to self-renewal during homeostasis and re-
pair. Cell, 135, 11181129. (2.) Laurenti E. et al. (2008).
Hematopoietic stem cell function and survival de-
pend on c-Myc and N-Myc activity. Cell Stem Cel, 3,
611624 . (3.) Essers MAG. (2009). IFNa activates dor-
mant HSCs in vivo. Nature, 458, 904908. (4.) Trumpp
A. (2010). Awakening dormant haematopoietic stem
cells. Nature Rev Immunol, 10, 201209.
The adult bone marrow harbors a reservoir of dormant HSCs.
Although dormant HSCs do not contribute to the day-to day
generation of new blood cells, they are efciently and rever-
sibly activated in response to bone marrow stress induced, for
example, by chemotherapeutic agents (5-FU) or toxic substan-
ces (such as BrdU).
Stem Cells and Cancer
Division
Stem Cells and Cancer (A010)
Managing Director of the Heidelberg
Institute for Stem Cell Technology and
Experimental Medicine (HI-STEM gGmbH)
69120 Heidelberg
Tel: +49 6221 42 3901
E-Mail: a.trumpp@dkfz.de
Analyses of the molecular processes taking
place during embryonic development have
shown that the principles guiding embryonic
development in humans and in animals are
very similar on a molecular level. Today it is
known that genes involved in the development
also play a role in human diseases. The Division
of Molecular Embryology is studying mecha-
nisms regulating cell differentiation. The aim
is to characterize molecular mechanisms
relevant for the formation of the body axis in
frogs and mice. To this end, we are identifying
developmental control genes and investigating
how these are regulated and what their func-
tions are. Our special interest is investigating
the mechanisms of the Wnt signaling pathway
in this context.
Future Outlook:
Future research is aimed at identifying novel
Wnt pathway components, to study their role
and mechanism of action.
Two-headed Xenopus
embryo following
experimental
overstimulation of the
head inducer Dickkopf 1.
Head: Prof. Dr. Christof Niehrs
Molecular Embryology (A050)
69120 Heidelberg
Tel: +49 6221 42 4693
E-Mail: niehrs@dkfz.de
ESSENTIAL PUBLICATIONS: (1.) Cruciat CM. et al.
(2010). Requirement of prorenin receptor and vacu-
olar H+-ATPase mediated acidication for Wnt sig-
nalling. Science, 327, 459463. (2.) Bilic J. et al. (2007).
Wnt induces LRP6 signalosomes and promotes di-
shevelled-dependent LRP6 phosphorylation. Science,
316, 16191622. (3.) Davidson G. et al. (2005). Casein ki-
nase 1 couples Wnt receptor signaling to the cyto-
plasmic transduction apparatus. Nature, 438, 867
872. (4.) Glinka A. et al. (1998). Dickkopf-1 is a member
of a new family of secreted proteins and functions in
head induction. Nature, 391, 357362.
Molecular Embryology
Division
Research Program 34
The Division is working on the characterisation
of the genetic response of organisms and their
cells to external signals (growth factors, in-
ammation-related cytokines, carcinogens and
tumor promoters) employing newly generated
genetically modied mouse models (which
replicate features of human diseases) and cell-
and organ cultures derived thereof. We want
to dene and characterize altered gene func-
tions, which result in imbalanced signaling
pathways and downstream genetic programs
forming the basis for acquired capabilities of
uncontrolled cell growth, evasion of apoptosis,
sustained angiogenesis and nally enhanced
tissue invasion and metastasis. To date and
currently, we have applied genetically modi-
ed animal models, in vitro organ systems, and
genome-wide expression analyses in order to
decipher the individual functions of AP-1 sub-
units. Our study of individual AP-1 subunits, of
their regulation as well as the identication of
distinct targets genes and genetic programs
critically involved in cancer development and
progression has yielded major contributions
to our current understanding of genetic pro-
grams in physiological (e.g. embryogenesis,
vascular biology/angiogenesis, wound healing)
and pathological processes (chronic inam-
mation, tumorigenesis). In collaboration with
clinical partners these studies, accompanied
by analyses of human tumor samples, aim ul-
timately to dene novel molecular markers for
diagnosis and therapeutic intervention.
Future Outlook:
With the goal to bridge basic science and
translational research, in collaboration with
partners at the DKFZ, University Heidelberg
and external partners, our program will focus
on intra- and intercellular signaling path-
ways and downstream genetic programs in
cancer to develop and evaluate molecules
Signal Transduction and Growth Control
Divison
Head: Prof. Dr. Peter Angel
as potential biomarkers or drug targets. We
will utilize state-of-the-art methods includ-
ing modied transgenic mice, various tumor
models, interspecies heterologous co-culture
cell systems, genome-wide expression and
epigenetic analyses combined with systems
biological approaches, and molecular and cel-
lular biology to study tumor-relevant genetic
networks. We will focus on mechanisms of
cell-cell communication in wound healing, and
cross-talk between tumor cells and cells of the
microenvironment (endothelial-, mesenchy-
mal- and immune cells). The main attention
will be focused on (soluble) mediators of cell
communication as well as downstream signal-
ling pathways and genetic programs initiated
in the corresponding target cells.
The main projects concern:
1. Physiology and pathology of wound heal-
ing: controlling genetic programs of cell
proliferation, migration and differentia-
tion
2. Function of the cell surface protein podo-
planin in brain and skin tumors
3. Genetic and epigentic programs of tumor
angiogenesis and vessel physiology; role
of the tumor stroma
4. Function of the cell surface receptor RAGE
and its ligands (S100 proteins) in the regu-
lation of genetic programs in inamma-
tion and cancer
ESSENTIAL PUBLICATIONS: (1.) Szabowski A. et al.
(2000). c-Jun and JunB antagonistically control cy-
tokine-regulated mesenchymal-epidermal interac-
tion in skin. Cell 103, 745755. (2.) Hess J. et al. (2004).
Functions of AP-1 subunits: Quarrel and Harmo-
ny among Siblings. J. Cell Sci 117, 59655973. (3.) Geb-
hardt C. et al. (2008) RAGE signaling sustains inam-
mation and promotes tumor development; J Exp Med
205, 275285. (4.) Licht A.H. et al. (2010). Junb regu-
lates arterial contractility and cellular migration via
its direct target Myl9, J Clin Invest 120, 23072318.
Signal Transduction and Growth Control (A100)
69120 Heidelberg
Tel: +49 6221 42 4570
E-Mail: p.angel@dkfz.de
35 Research at DKFZ 2013
Immunohistological analysis of a mouse
liver tissue section showing induction of liver
progenitor cells (red) in response to chronic liver
damage in a murine model of inammation
driven liver carcinogenesis.
Research Program 36
Epigenetics
Division
Epigenetic mechanisms regulate the interpre-
tation of genetic information. As such, epige-
netics plays an important role in mediating
phenotypic plasticity. Important examples
include cellular differentiation, transformation
and aging, which all involve profound altera-
tions in phenotypic plasticity.
DNA methylation is the longest known and
best-characterized epigenetic modication. In
the human genome, approximately 40 million
cytosine residues are methylated in the con-
text of CG dinucleotides. Importantly, altered
DNA methylation patterns represent one of
the earliest and most consistent hallmarks of
human cancers. Hypermethylation-induced
silencing of tumor suppressor genes has been
documented in all cancers and can be reversed
by the use of DNA methyltransferase inhibi-
tors. This allows fundamentally new approach-
es in the clinical management of cancer.
Our research activities focus on the characteri-
zation of DNA methylation patterns in various
models of phenotypic plasticity ranging from
human tissue aging to caste specication in
honeybees. In addition, we are developing DNA
methyltransferase inhibitors as novel anti-
cancer drugs. Here, our activities range from
computer modelling to molecular biomarker
analysis in clinical trials. Lastly, we are also
establishing a new research focus on cytosine
RNA methylation to investigate the potential
function of this modication in the context of
epigenetic regulation.
Future Outlook:
The division will continue its focus on three
major topics, the role of DNA methylation in
phenotypic plasticity, the development of DNA
methyltransferase inhibitors and the function-
al characterization of RNA methylation. For the
analysis of DNA methylation patterns, we will
place strong emphasis on the use of next-gen-
eration sequencing technologies to establish
genome-wide methylation maps from various
model systems. For the development of DNA
methylation inhibitors, we will focus on the
further development of the azacytidine scaf-
fold and thoroughly investigate the extended
mode of action of 5-azacytidine and its deriva-
tives. For the functional characterization of
RNA methylation, we will combine a detailed
analysis of RNA methyltransferase knockout
models with a comprehensive characterization
of RNA cytosine methylation patterns by next-
genertion sequencing.
ESSENTIAL PUBLICATIONS: (1.) Lyko F. et al. (2010).
The honey bee epigenomes: differential methyla-
tion of brain DNA in queens and workers. PLoS Bi-
ol. 8, e1000506. (2.) Grnniger E. et al. (2010). Aging
and chronic sun exposure cause distinct epigenetic
changes in human skin. PLoS Genet. 6, e1000971. (3.)
Schaefer M. et al. (2010). RNA methylation by Dnmt2
protects transfer RNAs against stress-induced cleav-
age. Genes Dev. 24, 15901595. (4.) Schaefer M. et al.
(2009). Azacytidine inhibits RNA methylation at DN-
MT2 target sites in human cancer cell lines. Cancer
Res. 69, 81278132.
Head: Prof. Dr. Frank Lyko
Microscopic image
of cancer stem cells
expressing EGFP under
the control of the
OCT4-promoter.
Epigenetics (A130)
69120 Heidelberg
Tel: +49 6221 42 3800
E-Mail: f.lyko@dkfz.de
Systems Biology of Cellular Signal Transduction
Division
The goal of the division is to gain insights into
molecular mechanisms that regulate cellu-
lar decisions and to address their impact on
behavior at the tissue and organ level. When
these control mechanisms fail, cancer and
other diseases arise. Cellular responses are
regulated by a multitude of extracellular sig-
nals received by cell surface receptors. Within
cells the information is processed through
complex intracellular signaling networks that
in turn impinge on gene regulation and affect
metabolism to nally coordinate physiological
responses such as proliferation, survival and
differentiation. These responses operate on
very different time scales ranging from min-
utes to hours and days. Thus, it is essential to
examine key dynamic properties of biological
systems, which can be addressed by combining
the generation of quantitative time-resolved
data with mathematical modeling. Data-based
mathematical models enable rapid testing of
hypotheses to uncover deregulation in cancer
and to predict strategies of intervention in
diseases. In close collaboration with modeling
partners, methods for quantitative analysis of
signaling networks were developed and multi-
ple dynamic pathway models were established
yielding unexpected insights into regulatory
mechanisms of signaling pathways. The main
projects of the division address:
1. Unraveling principal mechanisms of
erythropoietin (Epo)-mediated cellular
decisions in the hematopoietic system.
2. Bridging from the cellular to the whole
organ level during liver regeneration.
3. Insights into altered regulation in cancer
and prediction of strategies for efcient
intervention in diseases (cancer, drug-in
duced liver injury, viral infection).
Future Outlook:
This knowledge will be used to establish in-
tegrated models of signaling pathways, to
link them to gene regulation as well as cell-
cell communication and to include cell cycle
progression and cell survival. Finally, integra-
tion into multi-scale models and whole body
models is aspired. Translational aspects are
strengthened through intensive collabora-
tions with clinical partners and companies in
the frame of large third party funded research
networks.
ESSENTIAL PUBLICATIONS: (1.) Schilling M. et al.
(2009). Theoretical and experimental analysis
links isoform-specic ERK signalling to cell
fate decisions, Mol Sys Biol, 334: 119136. (2.) Becker
V. et al. (2010). Covering a broad dynamic range:
information processing at the erythropoietin
receptor. Science, 328: 14041408. (3.) Raia V. et al.
(2011). Dynamic mathematical modeling of IL13-
induced signaling in Hodgkin and primary me-
diastinal B-cell lymphoma allows prediction
of therapeutic targets. Cancer Res., 71: 693704.
(4.) Bachmann J. et al. (2011). Division of labor by
dual feedback regulators controls JAK2/STAT5
signaling over broad ligand range. Mol Syst Biol.
7: 516.
Head: Prof. Dr. Ursula Klingmller
In erythroid progenitor cells the cell
membrane is visualized by staining
for transferrin receptor expression
(green) and the nucleus by staining
for DNA content (blue).
Systems Biology of Cellular Signal
Transduction (A150)
69120 Heidelberg
Tel: +49 6221 42 4481
E-Mail: u.klingmueller@dkfz.de
Research Program 38
Head: PD Dr. Tobias P. Dick
Redox Regulation
Division
Elevated generation of oxidants (reactive oxy-
gen species) is associated with inammation
and many age-related disorders, including ma-
lignancy. Correspondingly, oxidants have been
generally regarded as unwanted and damag-
ing products. However, more recently it has
become clear that some oxidants, in particular
hydrogen peroxide (H
2
O
2
), also play benecial
roles as signaling molecules in healthy cells.
Oxidants regulate adaptive stress responses
and cell fate decisions through post-transla-
tional modication of transcription factors and
other target proteins. In particular, the signal-
ing functions of oxidants are typically based
on the reversible oxidation of protein thiol
residues, leading to transient activation or in-
activation of individual enzymes. In our labora-
tory we are investigating signaling pathways
by which H
2
O
2
contributes to the regulation
of cellular physiology. We are interested in the
nature of redox alterations that accompany
chronic inammation and malignant growth.
Special attention is devoted to the molecu-
lar mechanisms by which oxidants achieve
specicity as signaling molecules. Another area
of focus is to uncover the spatio-temporal dy-
namics of oxidative processes in vivo.
Future Outlook:
The role of H
2
O
2
sensing and signaling in in-
ammation. H
2
O
2
is released during tissue
injury and may act as one of the early signals
for the recruitment and activation of immune
cells. Recently, we identied H
2
O
2
-sensitive pro-
teins involved in inammatory signaling. Our
aim is to elucidate the specic links between
inammatory activators, H
2
O
2
and immune ef-
fector mechanisms.
Redox homeostasis in tumor cells: Many, if not
most, tumor cells differ in redox homeostasis
compared to their normal counterparts. More
detailed understanding of these differences
may lead to new ideas as to how to interfere
with tumor growth.
Molecular mechanisms of oxidative signal-
ing: How are H
2
O
2
-sensitive signaling proteins
oxidized in an efcient and specic manner?
Growing evidence suggests that certain per-
oxidases act as primary oxidant receptors and
pass on oxidizing equivalents to specic target
proteins.
Monitoring redox changes in cells, tissues and
organisms: We recently developed genetically-
encoded biosensors for oxidized glutathione
and H
2
O
2
. A major application is to monitor re-
dox processes as they occur in the physiologi-
cal context of the whole organism.
Fundamental principles of redox homeostasis:
The glutathione system is central to eukary-
otic redox homeostasis and drug resistance
but remains incompletely understood. We are
combining redox imaging and reverse genetics
in the model eukaryote S. cerevisiae to reveal
the fundamental regulatory principles of the
glutathione system.
ESSENTIAL PUBLICATIONS: (1.) Albrecht S.C. et al.
(2011). In vivo mapping of hydrogen peroxide and
oxidized glutathione reveals chemical and regional
specificity of redox homeostasis. Cell Metab 14,
819829. (2.) Gutscher M. et al. (2008). Real-time
imaging of the intracellular glutathione redox
potential. Nat Meth 5, 553559. (3.) Kienast A. et al.
(2007). Redox regulation of peptide receptiv-
ity of major histocompatibility complex class I
molecules by ERp57 and tapasin. Nat Immunol 8,
864872. (4.) Schwertassek U. et al. (2007). Selective
redox regulation of cytokine receptor signal-
ing by extracellular thioredoxin-1. EMBO J 26,
30863097.
Redox Regulation (A160)
69120 Heidelberg
Tel: +49 6221 42 2320
E-Mail: t.dick@dkfz.de
Redox-sensitive cysteine residues (yellow)
can act as molecular switches.
Head: Prof. Dr. Stephan Herzig
Molecular Metabolic Control
Division
The department Molecular Metabolic Con-
trol is a common research unit between the
German Cancer Research Center (DKFZ), the
Center for Molecular Biology (ZMBH) at the
University of Heidelberg and the University
Hospital Heidelberg. The department is investi-
gating the molecular basis of severe metabolic
disorders, including the Metabolic Syndrome
and type 2 diabetes, and their roles in tumor
initiation and progression. The main causes of
these metabolic disorders are believed to be
malfunctions in the activity of genes regulat-
ing our metabolism. By analyzing the signal-
dependent activity of such genes in response
to hormonal, nutritional and inammatory
cues, we aim to dene disease-causing mal-
functions in glucose, fat and protein metabo-
lism, ultimately aiming at the identication of
genes and gene products which increase the
susceptibility to metabolic diseases. Subse-
quently, identied gene defects are tested for
their potential to serve as molecular connec-
tions between metabolic and tumor diseases
and as potential novel drug targets within
these disease entities. Thus far, we have al-
ready characterized a number of molecular
switches that are dysregulated under certain
metabolic conditions and promote aberrant
metabolism in diabetes and cancer
Future Outlook:
In the future, we will address the question if
and how the differential recruitment of spe-
cic transcriptional complexes to genomic tar-
get sites provides a molecular relay station for
nutritional, hormonal and inammatory sig-
nals in the control of energy homeostasis and
the pathogenesis of aging-associated diseases,
including diabetes and cancer. Specically, we
will investigate whether and how relevant
transcription factor complexes bridge metabo-
lism, inammation and tumor development
through the integrated control of metabolic
pathways, inammatory responses, and cell
fate decisions.
By using a translational research approach,
we anticipate unravelling clinically signicant
molecular determinants in the pathogenesis
of the Metabolic Syndrome and type 2 diabe-
tes that are directly coupled to an increased
cancer risk in these patients, thereby serving as
potential new therapeutic targets in metabolic
disorders.
In particular, we will focus on three main areas
1. Transcriptional networks, systemic lipid
distribution, and lipotoxicity
2. Molecular integration of inammation and
metabolism
3. Brown adipocyte stem cells and control of
energy homeostasis
ESSENTIAL PUBLICATIONS: (1.) Kulozik Ph. et al. (2011).
Hepatic deciency in transcriptional co-factor TBL1
promotes liver steatosis and hypertriglyceridem-
ia. Cell Metabolism, 13, 389400. (2.) Vegiopoulos A.
et al. (2010). COX-2 controls energy homeostasis in
mice by de novo recruitment of brown adipocytes.
Science, 328, 11581161. (3.) Lemke U. et al. (2008). The
glucocorticoid receptor controls hepatic dyslipidem-
ia through Hes1. Cell Metab., 8, 212223. (4.) Herzig S.
et al. (2001). CREB regulates hepatic gluconeogenesis
through the coactivator PGC-1. Nature, 413, 179183.
Lipid droplets (red)
in adipocytes serve
as main energy
supply for the body.
Molecular Metabolic Control (A170)
69120 Heidelberg
Tel: +49 6221 42 3581
E-Mail: s.herzig@dkfz.de
Research Program 40
Head: Prof. Dr. Hellmut Augustin
Vascular Oncology and Metastasis
Division
The Augustin laboratory studies the complex-
ity of interactions occuring between tumor
cells and blood and lymphatic vessels during
tumor progression and metastasis, most no-
tably as it relates to the growth of blood ves-
sels in tumors. Angiogenesis, the sprouting of
new blood vessels from existing vessels, is an
oncofetal process that occurs physiologically
during development and postnatal growth,
but in adults is mostly restricted to pathologi-
cal processes, which makes angiogenesis an
attractive target. Angiogenesis is characterized
by a distinct cascade of molecular and cellular
events, which enable cells of the vessel wall
(endothelial cells) to sprout from a pre-existing
capillary and to form new lumenized capil-
laries which anastomose to form a vascular
network that matures over time with the re-
cruitment of perivascular mural cells (smooth
muscle cells, pericytes). Molecules of the
Angiopoietin/Tie ligand/receptor family play
central roles in these processes. Our scientists
study the molecular mechanisms of Angiopoi-
etin/Tie signaling in blood and lymphatic ves-
sels and analyze the molecular and functional
properties of endothelial cells and pericytes
during physiological and pathological angio-
genesis and vessel remodeling. Given the criti-
cal roles of blood and lymphatic dysfunction
for numerous oncological and non-oncological
diseases, this work aimed at better under-
standing the complexity of vessel functions
has immediate translational implications for
subsequent therapeutic exploitation.
Future Outlook:
It is increasingly recognized that angiogenesis-
regulating molecules do not just control the
growth of blood and lymphatic vessels, but
also have critical maintenance functions in
the adult. Molecules of the Angiopoietin/Tie
ligand/receptor family exert gatekeeper func-
tions within the vascular system to control
tissue homeostasis and serve metabolic main-
tenance functions. Future work of the labora-
tory will be aimed at better understanding the
molecular mechanisms of the vessel wall in
the control of tissue homeostasis, most nota-
bly as it relates to maintenance and repair pro-
cesses. Experimental approaches include (i) the
vascular control of liver regeneration and liver
tumorigenesis, (ii) the role of blood vessels in
contributing to brotic tissue remodeling, (iii)
the role of the vasculature in controlling tis-
sue metabolism, including obesity, (iv) the role
of blood vessels during ageing and the role of
vessel wall resident and bone marrow-derived
stem cells during this process, and (v) the role
of blood vessels in mediating the metastatic
dissemination of circulating tumor cells. The
lab will further intensify its efforts to elucidate
the molecular and functional properties of the
least well understood cells of the vessel wall,
the perivascular pericytes, a cell type lining
the outer surface of capillaries. We will study
pericyte-endothelial interactions in depth to
unravel pericyte function during pathological
conditions including brosis and tumor pro-
gression.
ESSENTIAL PUBLICATIONS: (1.) Felcht M. et al. (2012).
Angiopoietin-2 differentially regulates angiogenesis
through Tie2 and integrin signaling. J. Clin. Invest., 122,
19912005. (2.) Kutschera S. et al. (2011). Differential
endothelial transcriptomics identies Semaphorin 3G
as a vascular class 3 semaphorin. Arterioscler. Thromb.
Vasc. Biol., 31, 151159. (3.) Alajati A. et al. (2008). Sphe-
roid-based engineering of a human vasculature in
mice. Nature Methods, 5, 439445. (4.) Fiedler U. et al.
(2006). Angiopoietin-2 sensitizes endothelial cells to
TNF-alpha and has a crucial role in the induction of
inammation. Nature Med., 12, 235239.
Vascular Oncology and Metastasis (A190)
69120 Heidelberg
Tel: +49 6221 42 1500
E-Mail: h.augustin@dkfz.de
Mouse pups are born with an avascular retina.
After birth, retinal blood vessels grow centrifugally
from the optic disc over a period of 6 to 8 days to
form a complex sheet-like capillary network that
eventually prunes and matures over time. Due to
its versatility and opportunities for high resolution
analysis, the postnatal retinal angiogenesis model
has developed as the most popular model to study
angiogenesis in vivo.
Head: Prof. Dr. Bruce Edgar
Cell Growth and Proliferation
Division
The precise control of cell proliferation is es-
sential for development in growing animals
and plants, and for tissue homeostasis in
adults. Loss of this control is a pre-requisite for
carcinogenesis. Research in Dr. Edgars group
focuses on the mechanisms that control cell
growth and proliferation using the Drosophila
model system. They use diverse molecular, ge-
netic and cytological approaches to discover,
and then characterize, genes and pathways
that regulate the growth and proliferation of
cells in vivo in several different organs and tis-
sue types in this small fruity. Genes discov-
ered in this way often prove to be oncogenes
or tumor suppressors in humans, and thus
these basic studies fuel more applied cancer
research. Ongoing projects address the control
of cell proliferation by the E2F, Retinoblasto-
ma, and APC/C complexes, the mechanism of
growth-dependent endoreplication cell cycles,
nutrient-regulated cell growth via the insulin-
TOR signaling network, and the regulation of
homeostatic and neoplastic growth in the ys
gut by intestinal stem cells.
Future Outlook:
The laboratory continues to focus on the regu-
lation of the cell growth and proliferation in
several cell types in Drosophila. The main pro-
jects concern:
Regulation of cell cycle exit during differ-
entiation
Cell cycle control by Hsp90 and the APC/C
ubiquitin ligase
Control of Endocycles by E2F and the CRL4
ubiquitin ligase
Growth regulation of the Endocycle
Mechanism of endocycling in murine
trophoblast giant cells
Intestinal stem cell control by cell signal-
ing pathways including Jak/Stat, EGFR/
Ras/MAPK, Hippo, and others
Whole-genome screens for regulators of
intestinal stem cell proliferation and dif-
ferentiation
Cell cycle controls in intestinal stem cells
and their progeny
Development of an in vitro intestinal
stem cell culture model
ESSENTIAL PUBLICATIONS: (1.) Jiang H. et al. (2009).
Cytokine/Jak/Stat signaling mediates regeneration
and homeostasis in the Drosophila midgut. Cell, 137,
13431355. (2.) Jiang H. et al. (2011). EGFR/Ras/MAPK
signaling mediates adult midgut epithelial home-
ostasis and regeneration in Drosophila. Cell Stem
Cell, 8, 8495. (3.) Shibutani S.T. et al. (2008). Intrin-
sic negative cell cycle regulation provided by PIP
box- and Cul4Cdt2-mediated destruction of E2f1 dur-
ing S phase. Dev Cell, 15, 890900.(4.) Shaw R.L. et al.
(2010). The Hippo pathway regulates intestinal stem
cell proliferation during Drosophila adult midgut re-
generation. Development, 137, 41474158.
Cell Growth and Proliferation (A220)
ZMBH
69120 Heidelberg
Tel: +49 6221 54 6827
E-Mail: b.edgar@dkfz.de
sSpi 24-96h AED
Stem cell tumors (green cells) in a
fruit y intestine caused by forced
activation of Spitz, a conserved EGF-
type growth factor. The y intestine
has many similarities to its human
counterpart, and is being used by
Dr. Edgars research group to
understand the genetic basis of
gastrointestinal tumorigenesis.
Research Program 42
Head: Prof. Dr. Hannah Monyer
Clinical Neurobiology
Division in Cooperation with
Heidelberg University Medical Center
The common theme of the lab projects regards
mechanisms underlying brain plasticity. One
effort is related to the differential contribu-
tion of distinct glutamate receptor subtypes
to short- and long-term synaptic plasticity and
the modulation of glutamate receptors by aux-
iliary proteins.
Furthermore we investigate the functional
role of GABAergic interneurons to learning and
memory. GABAergic interneurons are the prin-
cipal source of inhibition in the adult brain and
synchronize the activity of neuronal networks
with millisecond precision, a prerequisite for
most higher brain functions. Projects focusing
on GABAergic interneuron function are tightly
interlinked and include studies at the molec-
ular-cellular, network and behavioral level. We
identied molecular targets that are ideal to
manipulate GABAergic interneuron activity in
order to probe cell and network function. Thus,
we take recourse to genetically modied mice
with reduced GABAergic interneuron recruit-
ment or altered connectivity and study the ef-
fect for spatial coding and memory. We focus
on the hippocampal-entorhinal formation,
a brain structure that is required for spatial
navigation in rodents and episodic memory in
humans.Finally, we study plasticity resulting
from the integration of newborn neurons into
established postnatal networks. Neurogenesis
projects focus on genes involved in cell genera-
tion, migration and differentiation.
Future Outlook:
We will extend our ongoing investigations in
the following directions:
1. We will seek to unravel mechanisms by
which newly identied auxiliary proteins
modulate receptor signaling. We will de-
termine interacting domains between
auxiliary proteins and receptors. Fur-
thermore, we will establish whether the
expression of auxiliary proteins can be
modulated by activity.
2. Projects revolving around GABAergic in-
terneuron function will entail more local
genetic manipulation.
So far, the genetic manipulation affected
GABAergic interneurons in the whole forebrain
but it would be ideal to manipulate interneu-
rons selectively in the hippocampal-entorhinal
cortex formation. Furthermore, virus-mediated
gene expression of light-activated channels
(e.g. Channelrhodopsin) allows the reliable
on-line identication of GABAergic interneu-
rons in freely moving mice and subsequent
interference with the cellular activity during
behavioral performance. This approach opens
up possibilities to establish causal relation-
ships between GABAergic interneuron activity,
spatial coding and memory. Finally, we discov-
ered novel bidirectional GABAergic pathways
between hippocampus and medial entorhinal
cortex whose function for neuronal synchro-
nization between these two major brain areas
remains to be established. 3) Projects regard-
ing neurogenesis will focus on modication
of neurogenesis by environmental factors
and establish the functional signicance of
neurogenesis for hippocampal and olfactory
learning.
ESSENTIAL PUBLICATIONS: (1.) Melzer S. et al. (2012).
Long-range-projecting GABAergic neurons modulate
inhibition in hippocampus and entorhinal cortex.
Science. 335, 15061510. (2.) Engelhardt J. et al. (2010).
CKAMP44. A brain-specic protein attenuating short-
term synaptic plasticity in the dentate gyrus. Science,
327, 15181522. (3.) Korotkova T. et al. (2010). NMDA re-
ceptor ablation on parvalbumin-positive interneu-
rons impairs hippocampal synchrony, spatial rep-
resentations, and working memory. Neuron, 68,
557569. (4.) Allen K. et al. (2011). Gap junctions be-
tween interneurons are required for normal spatial
coding in the hippocampus and short-term spatial
memory. J. Neurosci., 31, 65426552.
Clinical Neurobiology (A230)
69120 Heidelberg
Tel: +49 6221 42 3100
E-Mail: h.monyer@dkfz.de
Head: Prof. Dr. Bernd Bukau
Chaperones and Proteases
Division
Our research aims at understanding the mo-
lecular basis of the intricate functional net-
work of chaperones and proteases responsible
for maintaining protein homeostasis in the
cytosol. Our main focus is on:
(1) Biogenesis of proteins. Concurrently with
their synthesis, nascent polypeptides are sub-
jected to enzymatic processing, chaperone-
assisted folding or membrane targeting, pro-
cesses for which the ribosome serves as dock-
ing platform of enzymes, targeting factors and
chaperones. We are dissecting these events
and the relationship between translation and
protein folding/assembly.
(2) Functional network of Hsp70 chaperone
machines. The Hsp70 chaperone network con-
stitutes a versatile cellular system regulating
protein conformation. We analyze the mecha-
nism of Hsp70 and co-chaperones in protein
quality control.
(3) Cellular strategies coping with protein
misfolding and aggregation. Protein aggrega-
tion is an organised process in vivo, leading to
deposition of aggregates at specic cellular
sites. We are determining parameters and fac-
tors controlling protein aggregation, and are
dissecting the mechanism of clearance of mis-
folded and aggregated proteins by chaperones
and proteases.
Future Outlook:
We will focus on three long-term topics:
1. Biogenesis of proteins. What are the
mechanisms of chaperone-assisted co-
translational protein folding? What is
the basis for functional orchestration
of ribosome-associated chaperones, en-
zymes and targeting factors? Is protein
assembly a co-translational process, in
which nascent chains of components of a
protein complex interact with other com-
plex components to achieve assembly.
Does the translation process itself control
protein assembly?
Chaperones and Proteases (A250)
ZMBH
69120 Heidelberg
Tel: +49 6221 54 6795
E-Mail: bukau@zmbh.uni-heidelberg.de
2. Functional network of Hsp70 chaperone
machines. How do J-proteins activate
the Hsp70 cycle? How do nucleotide ex-
change factors of the Hsp110 family coop-
erate with Hsp70 in protein quality con-
trol? How do Hsp70-J-proteins distinguish
the different categories of client proteins?
3. Cellular strategies coping with protein
misfolding and aggregation. What mech-
anisms mediate sorting of aggregation-
prone proteins into distinct deposits?
Which factors are responsible for clear-
ance of misfolded/aggregated proteins?
How do AAA+ chaperones and Hsp70 sys-
tems mediate protein disaggregation and
refolding? What is the basis for the triage
decision between degradation and refold-
ing of misfolded proteins?
ESSENTIAL PUBLICATIONS: (1.) Oh E. et al. (2011). Se-
lective ribosome proling reveals the cotranslation-
al chaperone action of trigger factor in vivo. Cell 147,
12951308. (2.) Erbse A. et al. (2006). ClpS is an essen-
tial component of the N-end rule pathway in Escher-
ichia coli. Nature. 439, 753756. (3.) Weibezahn J. et al.
(2004). Thermotolerance requires refolding of aggre-
gated proteins by substrate translocation through
the central pore of ClpB. Cell, 119, 653665. (4.) Tyed-
mers J. et al. (2010). Cellular strategies for controlling
protein aggregation. Nat. Rev. Cell Biol. 11, 777788.
Hsp70
Hsp100 Hsp100
inactive activated
protein aggregate
Mechanism of protein aggregate
dissolution through Hsp70/Hsp100
cooperation. The ring-shaped Hsp100 has
two structural states, one inactive and the
other activated. A molecular toggle keeps
the Hsp100 chaperone in the inactive
state. Hsp70 causes the toggle to ip,
thereby activating the Hsp100 chaperone.
In this state it can pull protein strands out
of the aggregate. The activation of Hsp100
is not permanent, with the chaperone
reverting to the repressed state after the
aggregate has dissolved.
Research Program 44
Head: Prof. Dr. Ana Martin-Villalba
Molecular Neurobiology
Division
Unraveling the complex functions of CD95 in
the central nervous system has been the main
focus of our research in the past years. In par-
ticular, we discovered the multiple roles played
by CD95 in different neural, immune and tu-
mor cells. We have identied the CD95 as a
major trigger of cell migration/invasion lead-
ing to recruitment of inammatory cells and
tumor progression. On the other side, CD95
crucially contributes to stem cell survival and
lineage differentiation. Our current research
focus on further characterisation of the role of
CD95 in stem cell homeostasis and response
to injury; the role of CD95-induced inamma-
tion in neurodegenerative diseases such as
Parkinson disease and autoimmune diseases;
and the role of CD95 in glioblastoma- and pan-
creatic adenocarcinoma-derived cancer stem
cells. To dissect CD95s biology we combine
biochemical and modern genomic technolo-
gies as well as cell biology and genetics in hu-
man cells and the mouse model systems.
Future Outlook:
Adult stem cells are found in every organ
and are involved in tissue homeostasis and
response to injury. More and more molecu-
lar players involved in regulation of stem cell
homeostasis are recognized as crucial deter-
minants of axonal regeneration and vice versa.
Our future research centers on understanding
this molecular program, with special focus on
the role of CD95/CD95 ligand, Wnt signals and
RNA translation/degradation. At an additional
level of complexity, we study the modulation
of these processes by the immune system.
Alteration of the default program controlling
stem cells proliferation, survival and differ-
entiation set the ground for tumor initiation.
Likewise, interaction of the immune system
with the tumor are crucial to tumor progres-
sion. Findings from adult stem cells will be
further examined in human cancer stem cells
and animal models of glioblastoma and pan-
creatic adenocarcinoma. Our research intends
to contribute to the identication of molecular
mechanisms involved in stem cells biology,
axonal regeneration and tumor initiation and/
or progression.
ESSENTIAL PUBLICATIONS: (1.) Letellier E. et al. (2010).
CD95-ligand on peripheral myeloid cells activates
Syk kinase to trigger their recruitment to the in-
ammatory site. Immunity 32, 240252. This article
was picked and evaluated by Faculty of 1000 with
a F1000 Factor of 6 http://f1000biology.com/arti-
cle/id/2629957. (2.) Corsini N. et al. (2009). The death
receptor CD95 activates adult neural stem cells for
working memory formation and brain repair. Cell
Stem Cell 5, 178190. (3.) Kleber S. et al. (2008). Yes
and PI3K bind CD95 to signal invasion of glioblasto-
ma. Cancer Cell, 13, 235248. This article was picked
and evaluated by Faculty of 1000 members with a
F1000 Factor of 3.2.http://f1000medicine.com/arti-
cle/id/1119774/evaluation. (4.) Sancho-Martinez I.
et al. (2009). Tyrosine phosphorylation and CD95: a
FAScinating switch. Cell Cycle 8, 838842.
Molecular Neurobiology (A290)
69120 Heidelberg
Tel: +49 6221 42 3766
E-Mail: a.martin-villalba@dkfz.de
Neurosphere derived from neural stem cells
from the subventricular zone of Nestin-
Cre-ERT2 iYFP reporter mice 24 hours after
tamoxifen induction.
Our group identies, characterizes and exploits
the molecular mechanisms that control gene
expression at the genetic and epigenetic level,
aiming to understand the chain of events by
which external signals are transferred into
the cell nucleus to regulate transcription of
specic genes. Focussing on the role of nuclear
noncoding RNA (ncRNA) in chromatin struc-
ture and epigenetic regulation, we found that
ncRNA has an impact on many chromatin-
mediated processes, linking both RNA and chro-
matin elds. We have discovered a novel RNA-
based strategy for epigenetic programming,
showing that ncRNAs are capable of forming
DNA:RNA triplexes with regulatory gene se-
quences. These triplex structures are speci-
cally recognized by the DNA methyltransferase
DNMT3b, thereby inducing DNA methylation
and transcriptional silencing. Other ncRNAs
guide histone modifying enzymes to specic
genomic sites, demonstrating that ncRNAs can
act as selective ligands for chromatin modify-
ing enzymes. Deciphering novel epigenetic
and metabolic control mechanisms of gene
expression will reveal how epigenetic defects
cause human diseases and will be instrumen-
tal in facilitating therapeutic strategies in the
future.
Future Outlook:
Evidence from a variety of experimental sys-
tems demonstrates that non-coding RNAs
(ncRNAs) play a signicant role in the control
of gene expression and epigenetic regula-
tion. It seems that ncRNAs are numerous and
highly adapted in roles that require specic
nucleic acid recognition without complex ca-
talysis, such as in guiding RNA modications
or in directing post-transcriptional regulation
of gene expression and chromatin structure.
We intend to identify ncRNAs involved in the
regulation of chromatin and transcription and
will investigate the mechanism by which these
ncRNAs regulate the function of transcription
factors and chromatin modifying enzymes. We
will perform genome-wide analyses to explore
with which proteins these regulatory RNAs
are associated and will validate their role in
key biological processes. We expect that in the
long term, these studies will lead to an under-
standing of the mechanisms that propagate
a specic chromatin structure through cell
division and will provide mechanistic insights
into the functions of ncRNAs in transcriptional
regulation.
ESSENTIAL PUBLICATIONS: (1.) Schmitz K.-M. et al.
(2010). Triplex formation between noncoding RNA
and DNA targets DNMT3b to regulatory gene re-
gions. Genes&Dev. 24, 22652269. (2.) Feng W. et al.
(2010). PHF8 activitates transcription of rRNA genes
through H3K4me3 binding and H3K9me1/2 demeth-
ylation. Nature Struct. Mol. Biol. 17, 445450. (3.) Zhou
Y. et al. (2009). Acetylation by hMOF regulates NoRC-
dependent heterochromatin formation, nucleosome
positioning and transcriptional silencing. Nature Cell
Biol. 11, 10101016. (4.) Mayer C. et al. (2006). Intergen-
ic transcripts regulate the epigenetic state of rRNA
genes. Mol. Cell 22, 351361.
Molecular Biology of the Cell II
Division
Head: Prof. Dr. Ingrid Grummt
Molecular Biology of the Cell II (A030)
69120 Heidelberg
Tel: +49 6221 42 3423
E-Mail: i.grummt@dkfz.de
Non-coding RNAs
act in concert with
chromatin modifying
enzymes to establish
distinct epigenetic marks
at transcriptionally
active and silent genes,
characterized by specic
nucleosome positions,
histone marks (Ac, Me),
and DNA methylation
(CH3).
Research Program 46
Head: Prof. Dr. Werner W. Franke
Cell Biology
Helmholtz Professorship
Cell morphology, character, function and in-
teraction with other cells are established and
predominantly determined by their architec-
tonic organization, i.e. the cytoskeleton, in both
normal and pathological states, in situ and in
cell culture. In particular, our studies focus on
the structural and molecular elements form-
ing the cytoplasmic lament systems, notably
the microlament bundles as well as the inter-
mediate-sized laments and their anchorage
structures, the dense plaques located on the
cytoplasmic sides of the cell-cell connecting
junctions, i.e. primarily the adhering junctions
and the desmosomes. We are extending and
completing our analyses of the major constitu-
ent molecules of these cell type-specic junc-
tions using biochemical and immunological
methods, including chemical cross-linking as
well as high-resolution immunouorescence
and immunoelectron microscopy. To this end,
we generate antibodies against cell type-
specic cytoskeletal molecules and examine,
in collaboration with pathologists, their diag-
nostic value for tumor cell typing, notably for
the identication of the specic primary tumor
of metastatic tumor cells. In addition, we have
recently demonstrated spontaneous and cu-
mulative syntheses of proteins that then can
be assembled to certain novel and semistable
structures, including cell-cell junctions, that
are able to transform out of histogenesis a
given tumor cell type directly to a novel differ-
ent tumor cell type.
Cell Biology (A991)
69120 Heidelberg
Tel: +49 6221 42 3212
E-Mail: w.franke@dkfz.de
Future Outlook:
The ongoing and future work aims at the com-
pletion of the molecular composition of the
cell-cell junctions, their specic functions and
the elucidation of their value in tumor diag-
nosis.
ESSENTIAL PUBLICATIONS: (1.) Franke W.W. et al.
(2012). Diverse types of junctions containing tight
junction proteins in stratied mammalian epithelia.
Ann. N. Y. Acad. Sci., 1257, 152157. (2.) Franke, W.W. et al.
(2011). Mesenchymal-epithelial transitions: Sponta-
neous and cumulative syntheses of epithelial mark-
er molecules and their assemblies to novel cell junc-
tions connecting human hematopoietic tumor cells
to carcinomatoid tissue structures. Int. J. Cancer, 129,
2588-2599. (3.) Straub B.K. et al. (2011). EN-cadherin
heterodimers dene novel adherens junctions con-
necting endoderm-derived cells. J. Cell Biol., 195, 873-
887. (4.) Pieperhoff S. et al. (2012). The plaque pro-
tein myozap identied as a novel major component
of adhering junctions in endothelia of the blood and
lymph vascular systems. J. Cell. Mol. Med., 16, 1709-
1719.
Double-label immunouorescence
microscopy of a monolayer culture of
epithelial cells (human keratinocytes of line
HaCaT) connected by cell-cell bridges with
central desmosomes (red and yellow show
the major molecule, desmoplakin) anchoring
bundles of keratin laments (green).
Head: Prof. Dr. Gnther Schtz
Molecular Biology of the Cell I
Helmholtz Professorship
Molecular Biology of the Cell I (A992)
69120 Heidelberg
Tel: +49 6221 42 3411
E-mail: g.schuetz@dkfz.de
Our laboratory is studying the role of nuclear
receptors during normal development and
disease. Since germline-inactivation of the
mineralocorticoid receptor (MR) or the gluco-
corticoid receptor (GR) gene results in early
lethality, we generated mutant mice with
neuron-specifc inactivation of either gene in
the forebrain. To avoid effects on brain devel-
opment we established a transgenic mouse
line that allows inducible gene inactivation in
adult forebrain neurons.
The subventricular zone (SVZ) of the lateral
ventricle and the subgranular zone (SGZ) of
the dentate gyrus (DG) are the largest germi-
nal zones of sustained neurogenesis during
adulthood. We found that the orphan nuclear
receptor tailless (Tlx) is exclusively expressed
in these slowly dividing neural stem cells
(NSCs). We found that overexpression of Tlx
induced expansion of the neural stem cell
population in mice. These cells initiate the de-
velopment of glioma-like lesions and gliomas.
Glioma development is accelerated upon loss
of the tumor suppressor p53 in adult neural
stem cells. Therefore our goal is to generate
transgenic mouse models that will allow for
elucidation of the molecular mechanisms in-
volved in disease development.
In a novel project we study the function of
microRNAs in adult neural stem cells and neu-
rons, their impact on neural plasticity and their
involvement in the CNS control of energy bal-
ance and metabolism.
Future Outlook:
The major aims in our future work will be:
genome-wide identication of binding
sites of the mineralo- and glucocorticoid
receptor in the hippocampus.
characterization of Tlx target genes in the
subventricular zone and the subgranular
zone by ChIP-Seq methodology. With this
method we will identify the regulatory se-
quences that cause spatial and temporal
expression of the target genes of these
nuclear receptors. We anticipate that with
these approaches, chromatin immunopre-
cipitation coupled to massively parallel
sequencing, the characterization of target
genes for these nuclear receptors (GR, MR
and Tlx) will be possible. These efforts will
thus lead to a molecular understanding of
the action of these regulatory factors.
ESSENTIAL PUBLICATIONS: (1.) Tuckermann J.P. et al.
(2007). Macrophages and neutrophils are the targets
for immune suppression by glucocorticoids in con-
tact allergy. J. Clin. Invest., 117, 13811390. (2.) Engblom
D. et al. (2008). Glutamate receptors on dopamine
neurons control the persistence of cocaine-seek-
ing. Neuron, 59, 497508. (3.) Liu H.-K. et al. (2010).
The nuclear receptor tailless induces long term neu-
ral stem cell expansion and brain tumor initiation.
Genes. Dev., 24, 683695. (4.) Habermehl D. et al.
(2011). Glucocorticoid activity during lung maturation
is essential in mesenchymal and less in alveolar epi-
thelial cells. Mol. Endocrinol., 25, 12801288.
The glucocorticoid receptor
modulates transcription by
different modes of action.
glucocorticoids
GR
GRE
nGRE
P
P
AP1 or NF B
STAT5
STAT5
+
+
-
-
Research Program 48
Centrosomes of mammalian and fungi cells
play a decisive role in the temporal and spa-
tial organisation of the microtubules of the
bipolar spindle, which segregates the sister
chromatids to opposite poles of the cell during
mitosis. In addition, a large body of evidence
suggests that centrosomes also function as a
signalling platform that integrates a multitude
of cellular signals to control cell fate determi-
nation and/or cell cycle progression. Our lab
has a long-standing interest in understanding
how centrosome-associated components con-
trol mitotic exit and cytokinesis on a molecular
level. Our work has signicantly contributed to
the identication and molecular characterisa-
tion of a centrosome-associated mitotic check-
point, named as the spindle position check-
point (SPOC). This checkpoint stops cell cycle
progression in response to mis-orientation of
the mitotic spindle along the mother-daughter
cell polarity axis. More recently, a similar cen-
trosome-based SPOC mechanism was reported
to exist in higher eukaryotic cells undergo-
ing asymmetric cell divisions. This highlights
an important functional conservation, which
is currently being explored by our group. In
addition, we are investigating the molecular
mechanisms by which two conserved centro-
some-associated cell cycle regulators, the NDR
Head: Dr. Gislene Pereira
Molecular Biology of Centrosomes and Cilia
Helmholtz University Junior Research Group
Molecular Biology of Centrosomes and Cilia
(A180)
69120 Heidelberg
Tel: +49 6221 42 3447
E-Mail: g.pereira@dkfz-heidelberg.de
Cell division imaged
in the budding yeast
Saccharomyces
cerevisiae. The
chromosomes are
shown in blue, the
mitotic spindle
in green and the
centrosome.
kinase Dbf2 and the phosphatase Cdc14, regu-
late cytokinesis (i.e. the physical separation of
mother and daughter cells) after completion
of mitosis.
Future Outlook:
In all eukaryotic cells, mitotic checkpoints and
the temporal and spatial control of cytokinesis
are of extreme importance for the mainte-
nance and the accurate segregation of the
genome. Therefore, the molecular characteri-
sation of SPOC signalling and cell cycle control
of cytokinesis will constitute an important
part of our future research. In addition, over
the last ve years, we became interested in
investigating how specialised sub-structures
of centrosomes, named centrioles, serve as a
template for the formation of the basal body,
from which cilia and agella are assembled.
Cilia are highly conserved microtubule-based
organelles that play an essential role in signal-
ling and cell motility. Defects in the forma-
tion or function of cilia are related to a large
number of severe genetic disorders, known as
ciliopathies. Our aims are to understand the
molecular mechanisms that control the transi-
tion from centriole to basal body and how cilio-
genesis is coordinated with cell cycle progres-
sion in mammalian cells.
For more information about our research
activities, please visit our website:
www.dkfz.de/en/celldivision/index.php
ESSENTIAL PUBLICATIONS: (1.) Caydasi A.K. et al.
(2012). A dynamical model of the spindle position
checkpoint. Mol. Syst. Biol., 8, 582. (2.) Caydasi A.K. et
al. (2009). Spindle alignment regulates the dynam-
ic association of checkpoint proteins with yeast spin-
dle pole bodies. Dev Cell., 16, 146156. (3.) Bertazzi D.L.
et al. (2011). The cortical protein Lte1 promotes mitot-
ic exit by inhibiting the spindle position checkpoint
kinase Kin4. J. Cell Biol., 193, 10331048. (4.) Meitinger
F. et al. (2011). Phosphorylation-dependent regulation
of the F-BAR protein Hof1 during cytokinesis. Genes
& Dev., 25, 875888.
Head: Dr. Georg Stcklin
Posttranscriptional Control of Gene Expression
In eukaryotes, the activity of all genes depends
on the level of transcription in the nucleus.
In addition, many genes are regulated at the
post-transcriptional level by mechanisms that
control the translation efciency and degra-
dation rate of individual mRNAs in the cyto-
plasm. This allows cells to respond rapidly to
external stimuli and alter protein expression
levels directly. Our lab examines mRNA decay
and translation control in human cell lines and
mouse macrophages. We have extensively ana-
lyzed a group of unstable mRNAs that contain
adenylate-urylate(AU)-rich elements and the
cognate RNA-binding proteins that regulate
the stability of these mRNAs. Recent acitivies
in the lab focus on a novel class of destabiliz-
ing elements that form stem-loop structures.
Both elements are critical for suppressing cy-
tokine expression in macrophages and balanc-
ing pro- with anti-inammatory activites. We
have also identied a group of mRNAs whose
translation is specically regulated in activated
macrophages and current experiments ad-
dress the molecular mechanisms underlying
this type of regulation. Cells exposed to envi-
ronmental stress respond by reducing their
global rate of translation. Recently, we discov-
ered that translation suppression in response
Posttranscriptional Control of Gene Expression
(A200)
69120 Heidelberg
Tel: +49 6221 54 6887
E-Mail: g.stoecklin@dkfz-heidelberg.de
to cold shock is mediated via an unusual path-
way and is essential for cells to survive hypo-
thermia, underlying the importance of post-
transcriptional control mechanisms.
Future Outlook:
Future work in the lab will focus on identify-
ing novel cis-acting elements and trans-acting
factors that control both the degradation and
translation of specically regulated mRNAs. In
addition, we examine the mechanisms respon-
sible for suppressing global protein synthesis
in response to enviromental stress signals.
ESSENTIAL PUBLICATIONS: (1.) Hofmann S. et al.
(2012). Translation suppression promotes stress gran-
ule formation and cell survival in response to cold
shock. Mol Biol Cell., 23, 37863800. (2.) Spasic M. et
al. (2012). Genome-wide assessment of AU-rich el-
ements by the AREScore algorithm. PLoS Genet.,
8(1):e1002433. doi: 10.1371/journal.(3.) Sandler H. et al.
(2011). Not1 mediates recruitment of the deadeny-
lase Caf1 to mRNAs targeted for degradation by tris-
tetraprolin. Nucleic Acids Res., 39, 43734386. (4.)
Stoecklin G. et al. (2004). MK2-induced tristetrapro-
lin:14-3-3 complexes prevent stress granule associa-
tion and ARE-mRNA decay. EMBO J., 23, 13131324.
During cold shock,
mammalian cells suppress
protein synthesis.
Translationally arrested
mRNAs assemble into
stress granules (cyan) in
the cytoplasm and the
mitochondrial network
(green) shows severe
alterations. Nuclei are
visualized in purple.
Research Program 50
Cellular Senescence (A210)
69120 Heidelberg
Tel: +49 6221 42 4631
E-Mail: t.hofmann@dkfz-heidelberg.de
Head: Dr. Thomas G. Hofmann
The DNA damage response (DDR) is at the
heart of cancer etiology. Cancer cells show a
dysfunctional DDR which is associated with
increased genomic instability and resistance
to DNA damage-inducing treatments. Cells re-
spond to DNA damage by tipping the cell fate
balance to achieve one of the following out-
comes: DNA repair, cellular senescence, or cell
death. Commitment to a particular cell fate is
regulated by an evolutionary conserved signal
transduction network which is coordinated by
a set of DNA damage-responsive checkpoint
kinases. Our research group is studying the
regulatory processes controlling cell fate deci-
sions in response to DNA damage. Our aim is
to elucidate the molecular mechanisms un-
derlying the selectivity of the cellular decision
process in response to damage insults, which
could vary between DNA repair, cell death, and
senescence. To this end, we are identifying
novel regulators and substrates of checkpoint
kinases, and investigating their biological func-
tion and mechanism of action in the DDR net-
work. We have a particular interest in under-
standing the function of proteins localizing to
specic nuclear domains termed Promyelocytic
leukemia (PML) bodies. Indeed, PML bodies
have been proposed to act as nuclear cell fate
regulatory centers.
DNA damage checkpoint kinases (red & green)
are recruited to DNA double-strand breaks at
chromatin (blue) following ionizing radiation.
Future Outlook:
Our goal is to yield sufcient insight into cell
fate control mechanisms in order to dene
molecular targets which will allow us to mod-
ulate the DDR in cancer cells, and subsequently
channel it towards cell elimination.
ESSENTIAL PUBLICATIONS: (1.) Crone J. et al. (2011).
Zyxin is a critcal regulator of the apoptotic HIPK2-p53
signaling axis. Cancer Res., 71, 23502359. (2.) Winter
M. et al. (2008). Control of tumor suppressor HIPK2
stability by ubiquitin ligase Siah-1 and checkpoint
kinases ATM and ATR. Nature Cell Biology, 10, 812
824 (3.) Milovic-Holm K. et al. (2007). FLASH links the
CD95 signaling pathway to the cell nucleus and nu-
clear bodies. EMBO J., 26, 391401 (4.) Hofmann T.G.
et al. (2002). Regulation of p53 activity by its inter-
action with Homeodomain-interacting protein ki-
nase-2. Nature Cell Biology, 4,110
Cellular Senescence
Junior Research Group
Head: Dr. Hai-Kun Liu
Normal and Neoplastic CNS Stem Cells
Active adult neurogenesis is one of the most
exciting discoveries in neuroscience of the
last decade. The subventricular zone (SVZ) of
the lateral ventricle (LV) and the subgranular
zone (SGZ) of the dentate gyrus (DG) in the
hippocampus are the largest germinal zones
of sustained neurogenesis during adulthood
in the mammalian central nervous system.
Astrocyte-like type B cells in the adult SVZ are
thought to be multipotent neural stem cells
(NSCs). These cells give rise to transient ampli-
fying type C cells, which in turn differentiate
into type A cells (neuroblasts) that migrate to
the olfactory bulb (OB) through the rostral mi-
gratory stream (RMS). NSCs in the SGZ mainly
give rise to new granular cells in the DG which
are thought to be important for spatial learn-
ing and memory. Adult neurogenesis in the
SVZ represents a unique system to study regu-
lation of NSC proliferation, differentiation and
directed neuronal migration in vivo. Strikingly,
these cells can also initiate gliomagenesis af-
ter acquiring the same oncogenic mutations
which were found in human brain tumor pa-
tients. Our lab aims to identify crucial molecu-
lar pathways that are important for the regu-
lation of normal and neoplastic neural stem
cells. To achieve this goal, we are mainly using
mouse models in which we have altered the
activity of some oncogenes, tumor suppressors
and chromatin remodellers specically in adult
mouse neural stem cells.
Future Outlook:
We have generated several mouse models
which can be used to introduce genetic muta-
tions specically in NSCs. We are currently us-
ing these models to study:
1. Genetic and epigenetic regulation of neu-
ral stem cells:
Epigenetic mechanisms are crucial for the
regulation of the most important charac-
teristics of stem cells that are self-renew-
al and multipotency.
Key transcriptional factors play decisive
roles in the determination of the identity
of stem cells and their progenies. One
of the major focuses in our lab is to un-
derstand the interplay between crucial
transcriptional factor and chromatin
remodelers, in particular their functions
during neural stem cell self-renewal and
differentiation.
2. Neoplastic neural stem cells:
One important issue of targeting brain-
tumor stem cells (BTSCs) is to avoid dam-
aging normal stem cells. Thus our goal is
to identify critical differences between
normal and tumor stem cells which will
provide important information for target-
ing exclusively BTSCs.
3. Mouse models of brain tumors:
We have developed several inducible
mouse brain tumor models by introduc-
ing frequently found genetic mutations in
human patients. We consider the induc-
ible model a better model to recapitulate
the human glioblastoma, and it will be
extremely interesting to further investi-
gate the cellular and molecular changes
before detectable brain tumor formation
in this particular model.
ESSENTIAL PUBLICATIONS: (1.) Liu H-K. et al. (2010).
The nuclear receptor tailless induces long-term neu-
ral stem cell expansion and brain tumor initiation.
Genes Dev 24, 683695. (2.) Liu H-K. et al. (2008). The
nuclear receptor Tailless is required for neurogenesis
in the adult subventricular zone. Genes Dev 22, 2473
2478. (3.) Belz T. et al. (2007). Inactivation of the gene
for the nuclear receptor tailless in the brain preserv-
ing its function in the eye. Eur J Neurosci 26, 2222
2227.
Newly derived immature
neurons (green) migrating
in the adult mouse olfactory
bulb (DAPI in blue).
Normal and Neoplastic CNS Stem Cells (A240)
69120 Heidelberg
Tel: +49 6221 42 3266
E-Mail: l.haikun@dkfz.de
Research Program 52
Head: Dr. Andreas Fischer
Vascular Signaling and Cancer
Blood vessels are a prerequisite for the main-
tenance of all organ functions. Embryogen-
esis is dependent on the development and
outgrowth of blood vessels, which provide the
organism with oxygen and nutrients. Sprout-
ing angiogenesis occurs rarely in the adult
organism but can be observed for example
during wound healing and also in cancer. Thus,
a detailed knowledge about factors regulat-
ing angiogenesis and genetic networks, which
provide a functional quiescent vascular bed,
is highly desirable. Besides the formation of
new blood vessels, maintenance of existing
blood vessels is also essential. Endothelial cells
provide the inner lining of all blood vessels.
Disturbed endothelial cell functions are impli-
cated in the pathogenesis of several cardiovas-
cular diseases. Importantly, tumor growth and
metastasis are strictly dependent on vascular
growth and remodeling.
Future Outlook:
Our research group investigates signaling
pathways that keep blood vessels in a rest-
ing but fully functional state. We examine the
signaling interplay between endothelial cells
as well as interactions of endothelial cells with
pericytes and tumor cells.Using cell culture
and animal models, our research will help to
better understand how genetic factors coordi-
nate angiogenesis in the adult organism. We
investigate the role of Delta-Notch signaling
and other genes, which are implicated in the
formation of vascular malformations and vas-
cular tumors. Other projects in our group focus
on barrier functions of blood vessels, which
are essential to control the passage of tumor
cells and uids through the vessel wall. A novel
research approach deals with the question of
how genetic alterations in the endothelium
affect metabolism and are implicated in the
pathogenesis of cardiovascular diseases. Our
research work aims at identifying critical mo-
lecular and cellular mechanisms of cardiovas-
cular diseases and tumor progression. These
ndings will help to lay the foundation for the
development of innovative pharmacological
strategies.
ESSENTIAL PUBLICATIONS: (1.) Wstehube J. et al.
(2010). Cerebral cavernous malformation protein
CCM1 inhibits sprouting angiogenesis by activating
DELTA-NOTCH signaling. Proc Natl Acad Sci U S A., 28,
1264012645. (2.) Brtsch R. et al. (2010). Integrin cy-
toplasmic domain-associated protein-1 attenuates
sprouting angiogenesis. Circ Res., 5, 592601. (3.) Fis-
cher A. et al. (2007). Combined loss of Hey1 and HeyL
causes congenital heart defects because of impaired
epithelial to mesenchymal transition. Circ Res., 6,
856863. (4.) Fischer A. et al. (2004). The Notch target
genes Hey1 and Hey2 are required for embryonic vas-
cular development. Genes Dev., 8, 901911.
Small blood vessels of the
retina with some covered by
pericytes (black).
Vascular Signaling and Cancer (A270)
69120 Heidelberg
Tel: +49 6221 42 4150
E-Mail: a.scher@dkfz.de
Head: Dr. Marieke Essers
Stress-induced Activation of Hematopoietic
Stem Cells (A011)
German Cancer Research Center and
Heidelberg Institute for Stem Cell Technology
and Experimental Medicine
(HI-STEM gGmbH)
69120 Heidelberg
Tel: +49 6221 42 3919
E-Mail: m.essers@dkfz.de
Stress-induced Activation of Hematopoietic
Stem Cells
HI-STEM Junior Research Group
Tissue stem cells are responsible for the main-
tenance and repair of most organs and tissues.
In the hierarchically organized blood system,
dormant hematopoietic stem cells (HSCs) with
life long self-renewal capacity are at the top of
this hierarchy of cell types which give rise to
active HSCs that typically control the blood cell
production during healthy homeostasis. How-
ever, under conditions of stress, such as during
virus infections or after blood loss, where large
amounts of mature blood cells are lost, feed-
back signals are thought to signal back to the
dormant HSCs, leading to their activation and
thus production of new mature blood cells.
However, the molecular and cellular mecha-
nisms, including those cytokines as a part of
these feedback loops, remain largely unex-
plored. Our work has recently demonstrated
that the cytokine IFN which is produced by
virally infected immune cells to block the in-
fection of more mature blood cells, is able to
activate the entire HSC pool including dormant
ones. One of the goals of our research is to
investigate the mechanism of IFN-mediated
activation of HSCs and the potential role of
the surrounding bone marrow stem cell niche
in this process. Furthermore, we are currently
exploring feedback loops in response to other
stress situations, like bacterial infection and re-
sponse to chemotherapy induced cytopenia.
Future Outlook:
Leukemias are initiated and maintained by leu-
kemic stem cells (LSCs), which can transplant
the disease and show unlimited self-renewal
activity. Most importantly, LSCs appear to be
resistant to conventional therapies including
anti-proliferative chemotherapy. The mecha-
nisms responsible for this resistance remain
unclear, however, their often dormant status
as well as their localization in protecting stem
cell niches are likely critical components. In
our group we address whether LSCs can be
targeted by driving them out of dormancy and
mobilize them out of their niche. Our nding
that IFN activates normal HSCs to self-renew
by putatively altering their niche interactions,
may open new possibilities to combine this
drug with tyrosine kinase inhibitors such as
Imatinib/Gleevec. This class of targeted thera-
pies can achieve long term remission by elimi-
nating progenitor and mature leukemic cells
(as with chemotherapy alone), but spare the
LSCs (see gure) and thus do not lead to cure.
Using mouse models for leukemia and by test-
ing leukemic patient samples, we are currently
exploring whether combination therapies with
IFN or other activators can be developed to
also target LSCs and thus potentially cure the
disease.
ESSENTIAL PUBLICATIONS: (1.) Essers M.A. et al.
(2009). IFNalpha activates dormant haematopoietic
stem cells in vivo. Nature, 458, 904908.
(2.) Trumpp A. et al. (2010). Awakening dormant
haematopoietic stem cells. Nat Rev Immunol., 10,
201209. (3.) Essers M.A. et al. (2010). Targeting leuke-
mic stem cells by breaking their dormancy. Mol On-
col., 4, 443450. (4.) Glauche I. et al. (2012). Therapy of
chronic myeloid leukaemia can benet from the ac-
tivation of stem cells: simulation studies of different
treatment combinations. Br J Cancer, 106, 17421752.
+chemotherapy
a.
resistant
dHSC
dLSC
G
0
dHSC
dLSC
G
0
+chemotherapy
b.
aLSC dLSC
G
0
+IFN
???
Like normal hematopoietic stem cells (HSCs), most leukemic stem cells (LSCs) are resistant to anti-
proliferative chemotherapy (a). Their resistance is believed to be the cause of relapse of the leukemia.
Several reasons for this resistance have been suggested, one of them being the dormant status of LSCs.
Thus, if dormancy is a main reason for LSC resistance to chemotherapy, one can postulate a two-step
therapy model by which the dormant LSCs can be targeted; activation of dormant LSCs by activators of
quiescence such as IFNa, followed by targeted chemotherapy (b). Such a therapy would not only reduce
the bulk of the leukemia, but also eliminate the dormant LSCs, thus reducing the chances of a relapse of
the leukemia.
Research Program 54
Head: Dr. Michael Milsom
Experimental Hematology
Experimental Hematology (A012)
(HI-STEM gGmbH)
69120 Heidelberg
Tel: +49 6221 42 3920
E-Mail: m.milsom@hi-stem.de
Transplantation of hematopoietic stem cells
(HSC) is a potential curative therapy for many
inherited blood disorders and, in concert with
high dose chemo- or radiotherapy, can be ef-
fective in the treatment of a range of cancers.
A major limitation of this approach is the lack
of availability of an immunologically matched
HSC donor. The work of the Experimental He-
matology Group focuses on dissecting the bi-
ology of HSC in order to facilitate the produc-
tion of transplantable HSC from novel sources,
and to better understand the regulation of
both normal and leukemic stem cells at the
molecular level. To these ends, we have devel-
oped several novel model systems to screen for
cellular factors that either have a major impact
on the formation of HSC during development
(HSC specication); or which regulate the abil-
ity of HSC to give rise to daughter cells that
have the same stem cell properties as the par-
ent cell (HSC self-renewal). The latter process is
essential for the maintenance and expansion
of HSC numbers and is also deregulated in leu-
kemic stem cells. In order to interrogate HSC
self-renewal, we primarily focus upon the com-
parative biology of HSC isolated from normal
wild type mice versus those from mice that are
deleted for genes in the Fanconi anemia sig-
nalling pathway. This model system allows us
to directly compare normal versus deregulated
HSC self-renewal.
Future Outlook:
As we gradually dissect the mechanisms that
regulate HSC biology, we anticipate that this
knowledge will have a direct impact upon both
our understanding of cancer and its treatment
in the clinic. Normal adult stem cells and can-
cer cells have a number of features in common
(unlimited proliferation capacity, restricted
differentiation, drug resistance) and under-
standing which signalling pathways mediate
these biological processes should allow us to
identify new therapeutic targets to eliminate
or restrict tumor cell growth. Our focus on
how normal stem cells regulate their genetic
integrity (using the Fanconi anemia model)
gives us new insight into how tumor cells may
evolve from normal healthy cells, which in turn
may allow us to advance strategies employed
in preventative medicine. Finally, by develop-
ing new methodologies to manipulate, expand
and differentiate stem cells, we can signicant-
ly contribute to the emerging eld of cell and
gene therapy, which is showing some promise
in early clinical trials directed against a num-
ber of diseases, including cancer.
ESSENTIAL PUBLICATIONS: (1.) Geiselhart A. et al.
(2012). Disrupted signalling through the Fanconi ane-
mia pathway leads to dysfunctional hematopoiet-
ic stem cell biology: underlying mechanisms and po-
tential therapeutic strategies. Anemia, 2012: 265790.
(2.) Mller L.U.W. et al. (2012). Overcoming reprogram-
ming resistance of Fanconi anemia cells. Blood. 119
(23):pp5449-57. (3.) Milsom M.D. et al. (2009). Ectop-
ic HOXB4 overcomes the inhibitory effects of tumor
necrosis factor- on Fanconi anemia hematopoiet-
ic stem and progenitor cells. Blood, 113 (21): pp5111-20.
(4.) Milsom M.D. et al. (2009). Fanca-/- hematopoietic
stem cells demonstrate a mobilization defect which
can be overcome by administration of the Rac inhibi-
tor NSC23766. Haematologica, 94 (7): pp1011-15.
The in vitro specication of
hematopoietic progenitor cells
from murine embryonic stem
cells. Using this methodology,
ES cells are able to differentiate
into a range of hematopoietic
progenitor cell types including
myeloid precursors such
as colony forming unit
granulocyte / macrophage
(CFU-GM) and erythroid
precursors such as erythroid
burst forming units (BFU-E).
Head: Dr. Christoph Rsli
Biomarker Discovery (A013)
(HI-STEM gGmbH)
69120 Heidelberg
Tel: +49 6221 42 3917
E-Mail: C.Roesli@dkfz.de
Biomarker Discovery
Targeted cancer therapeutics, such as imatinib
and rituximab, have shown striking success in
the therapy of blood cancers. Unfortunately,
the majority of cancer patients still have to be
treated with conventional, unspecic chemo-
therapeutics. Due to their systemic distribu-
tion, these therapies carry severe side effects.
The disadvantages of conventional chemo-
therapeutics could be circumvented by the
targeted delivery of bioactive molecules to
the tumor. Drugs can be exclusively delivered
to disease sites by conjugation to molecules
specically binding to tumor-associated bio-
markers. Such ligand-based vascular targeting
strategies crucially rely on:
1) the identication of robust vascular-accessi-
ble tumor biomarkers,
2) the availability of antibodies or fragments
thereof with high afnities to these tumor-
specic biomarkers and
3) the coupling of these antibodies to bioactive
moieties.
The HI-STEM/DKFZ-Junior Research Group
Biomarker Identication is focusing on the
mass spectrometry-based identication of
novel biomarkers expressed in tumorous tis-
sue and/or metastases using advanced cell
culture systems, xenograft tumor models and
clinical samples. Furthermore, the selection of
human monoclonal antibodies against these
biomarkers for the development of targeted
cancer therapies and novel diagnostic tools is
a core technology in the laboratory.
Future Outlook:
During recent years, the concept of cancer
stem cells has evolved and is now widely ac-
cepted. Cancer stem cells (or tumor initiating
cells) are a small subpopulation of cancer cells
able to promote new tumors and to induce
metastases. Importantly, these cells are usu-
ally not reached by current cancer therapeutics
since they can reside ( just like their healthy
counterparts), at least transiently, in a dor-
mant, therapy-resistant phase. The popula-
tion of transiently dormant cancer stem cells
is furthermore most likely responsible for the
re-occurrence of tumors years after success-
ful treatment. Due to the lack of informa-
tion about the cell surface proteome of cancer
stem cells, no current therapeutic specically
affects this highly aggressive but well-pro-
tected cancer cell population. Our group will
use its established chemical proteomics-based
methods for the identication of cell surface
biomarkers on the rare population of cancer
stem cells. The resulting biomarkers are then
used to develop high afnity human monoclo-
nal antibodies by means of the phage display
technology. These antibodies are then not only
used for basic research, but also for the devel-
opment of diagnostics and novel innovative
targeted therapeutics. Future cancer therapies
might then be based on a two phase protocol:
a rst debulking phase for the reduction of the
tumor burden, followed by a targeted attack
on remaining, dormant cancer stem cells hid-
den elsewhere in the body.
ESSENTIAL PUBLICATIONS: (1.) Fugmann T. et al.
(2010). DeepQuanTR: MALDI-MS-based label-free
quantication of proteins in complex biological sam-
ples. Proteomics, 10, 26312643. (2.) Schliemann C. et
al. (2010). In vivo biotinylation of the vasculature in
B-cell lymphoma identies BST-2 as a target for an-
tibody-based therapy. Blood, 115, 736744. (3.) Fug-
mann T. et al. (2011). Proteomic identication of va-
nin-1 as a marker of kidney damage in a rat model
of type 1 diabetic nephropathy. Kidney Int., 80, 272
281. (4.) Rsli C. et al. (2009). Comparative analysis
of the membrane proteome of closely related meta-
static and nonmetastatic tumor cells. Cancer Res., 69,
54065414.
Following the proteomics-based
identication of a tumor-associated
biomarker, human monoclonal
antibodies are selected and used for
the development of novel diagnostic
tools and/or targeted therapeutics.
Research Program 56
Head: Dr. Thordur Oskarsson
Metastatic Niches
Metastatic Niches (A014)
(HI-STEM gGmbH)
69120 Heidelberg
Tel: +49 6221 42 3903
E-Mail: thordur.oskarsson@hi-stem.de
Metastasis is the spread of cancer cells from
their site of origin leading to outgrowth in
distant organs and is the cause of most cancer
related deaths. To progress into overt metas-
tasis, disseminated cancer cells must resist a
non-permissive environment and maintain
viability and growth at distant sites. Increas-
ing evidence suggests that cancer cells adapt
by engaging and manipulating the micro-
environment generating a metastatic niche
that promotes cancer cell tness. To study the
metastatic niche the Oskarsson lab utilizes 3D
culture systems of primary cancer cells, RNA
interference, transcriptomic and proteomic
screens and various mouse models of cancer
progression and metastasis. We have shown
that tenascin C (TNC), an extracellular matrix
(ECM) protein expressed in normal stem cell
niches, is an important component of the met-
astatic niche and advances metastatic progres-
sion in breast cancer. The production of TNC
promotes viability of metastasis initiating cells
by enhancing the expression of musashi-1, a
positive regulator of Notch signaling and by
inducing the Wnt target gene LGR5. We are
currently dissecting further the pathways
modulated by TNC and studying the surface
receptors that TNC engages. Moreover, we are
analyzing the signaling and functional role of
other metastatic niche components in cancer
progression with a focus on the ECM. These
studies may provide valuable insights into can-
cer progression and could reveal new targets
for therapeutic intervention.
Future Outlook:
Our aim is to identify new components of the
metastatic niche and to characterize the in-
teraction of cancer stem cells with the niche.
The objective is to determine how the niche
supports and maintains metastatic stem cell
characteristics and to study the possible role of
the niche in resistance to cancer therapy. It is
increasingly evident that stem cell properties
play an important role in metastasis develop-
ment and the niche may support and maintain
these features. We will pay particular attention
to the extracellular matrix (ECM) that has been
demonstrated by us and others to be an es-
sential component of the metastatic niche. The
function of the ECM extends greatly beyond a
structural scaffold and has been shown to be
important for cell regulation and modulation
of signaling pathways. The ECM components
of the metastatic niche support essential func-
tions in cancer progression and effectively help
cancer cells to colonize distant organs. Moreo-
ver, the metastatic niche may be a mode for
disseminated cancer cells to resist therapeutic
intervention. We will analyze the role of niche
components in resistance to cancer therapy,
an attribute that is tightly linked to meta-
static progression. The dissection of the meta-
static niche and the ECM mediated signaling
within the niche, could provide new avenues to
therapeutically impair the competence of dis-
seminated cancer cells and prevent metastatic
relapse.
ESSENTIAL PUBLICATIONS: (1.) Acharyya S. et al.
(2012). A CXCL1 paracrine network links cancer chem-
oresistance and metastasis. Cell. 150, 165178. (2.) Os-
karsson T. et al. (2011). Breast cancer cells produce
tenascin C as a metastatic niche component to col-
onize the lungs. Nat Med. 17, 867874. (3.) Oskarsson
T. et al. (2010). Diverted total synthesis leads to the
generation of promising cell-migration inhibitors for
treatment of tumor metastasis: in vivo and mecha-
nistic studies on the migrastatin core ether analog.
J Am Chem Soc., 132, 32243228. (4.) Tavazoie S.F. et
al. (2008). Endogenous human microRNAs that sup-
press breast cancer metastasis. Nature., 451, 147152.
Immunostaining of lung metastasis in breast
cancer xenograft showing expression of the
metastatic niche component tenascin-C at
the invasive front (arrow heads).
Head: Dr. Jakob von Engelhardt
Synaptic Signalling and Neurodegeneration
(A300)
69120 Heidelberg
Tel: +49 6221 423105
E-Mail: engelhardt@dkfz.de
DZNE = German Center for Neurodegenerative
Diseases within the Helmholtz Association
(Deutsches Zentrum fr Neurodegenerative
Erkrankungen in der Helmholtz-Gemeinschaft)
Synaptic Signalling and Neurodegeneration
DZNE-Junior Research Group
Our group investigates glutamatergic synaptic
transmission in the hippocampus and cortex.
We are particularly interested in what role dif-
ferent glutamate receptors (AMPA- and NMDA-
receptors) and glutamate receptor-interacting
proteins play in physiological and pathophysi-
ological processes. AMPA receptors mediate
most of the fast excitatory transmission in the
central nervous system. NMDA receptors are
important for synaptic plasticity and thus for
learning and memory. In addition, excessive
activation of NMDA receptors is detrimental
for neurons (excitotoxicity) and contributes to
the pathophysiology of brain diseases such as
stroke and neurodegenerative diseases.
Future Outlook:
1. Mechanisms of Amyloid pathology:
One of the hallmarks of Alzheimers
disease is the accumulation of amyloid
beta-peptide (A) in the brain and its
deposition as plaques. However, the cur-
rent prevailing view is that soluble oligo-
meric A is one of the main mediators of
Alzheimer neurotoxicity, rather than the
plaques. There are indications that gluta-
mate receptors play a role in A-mediated
neurotoxicity. We will use glutamate re-
ceptor transgenic mice to investigate the
inuence of this interaction on the physi-
ology and anatomy of hippocampal and
cortical neurons.
2. Regulation of synaptic communication via
AMPA-receptor interacting proteins:
Precise control of AMPA receptor number
and localization on the cell membrane
regulates synaptic strength and is thus
of great importance for all cognitive pro-
cesses. AMPA-receptor interacting pro-
teins (TARPs, CKAMP44, cornichons and
SynDig1) regulate receptor localization
and function. We will use heterologous
expression systems and transgenic mice
to analyze the inuence of those proteins
on the electrophysiological properties and
localization of AMPA-receptors.
ESSENTIAL PUBLICATIONS: (1.) von Engelhardt J. et al.
(2011). 5-HT3A Receptor-Bearing White Matter Inter-
stitial GABAergic Interneurons Are Functionally In-
tegrated into Cortical and Subcortical Networks. J
Neurosci, 31, 1684416854. (2.) von Engelhardt J. et
al. (2010). CKAMP44: a brain-specic protein atten-
uating short-term synaptic plasticity in the dentate
gyrus. Science, 327, 15181522. (3.) Korotkova T. et al.
(2010). NMDA receptor ablation on parvalbumin-pos-
itive interneurons impairs hippocampal synchrony,
spatial representations, and working memory. Neu-
ron, 68, 557569. (4.) von Engelhardt J. et al. (2008).
Contribution of hippocampal and extra-hippocampal
NR2B-containing NMDA receptors to performance on
spatial learning tasks. Neuron, 60, 846860.
Schematic representation of the 424 residue
CKAMP44 protein, with signal peptide (SP),
extracellular domain with cysteine-rich region (Cs),
single transmembrane region (TM) and intracellular
domain containing a PDZ domain interaction site
at the C-terminus. The extracellular cysteine-rich
region with proposed disulde bridges of a Cystine-
knot is shown below. The in situ hybridizations
illustrate that CKAMP44 mRNA is expressed in the
brain of embryonic day 19 (E19), postnatal day 15
(P15) and adult mice. The immunocytochemical
analyses of cultured neurons show that CKAMP44
is expressed in dendritic spines and co-localizes with
AMPA receptor subunits GluA2/3.
Functional and
Structural Genomics
Cancer arises when genes in a cell are changed in such a way that
they cause the cell to divide uncontrollably or to refrain from dying.
For this to happen, however, a multitude of specic changes have to
coincide. It is the task of this research program to analyze the geno-
me, i.e., the complete set of genes and its products, in order to lay
the foundation for developing new diagnostic and treatment me-
thods. This involves mapping the genome, localizing genes within
the genetic material, and investigating the functions of cancer-
relevant genomic areas. The vast amounts of data accumulated in
the process are being captured and evaluated using bioinformatic
methods. By combining approaches from mathematics, statistics,
physics, and computer sciences with computer-assisted simulation
techniques, the theoretical groups of the research program are
bridging the gap to experimental research. The methods developed
within the research program are being directly utilized in many
areas within collaborations with numerous divisions of the Center:
in molecular and genomic investigations of the structure of the
genetic material, cancer documentation, medical imaging, and bio-
statistical evaluations of experimental and clinical data.
Coordinator
PROF. DR. ROLAND EILS
58 Research Program
Research Program 60
Head: Prof. Dr. Manfred Schwab
Tumor Genetics
Division
Tumor Genetics (B030)
69120 Heidelberg
Tel: +49 6221 42 3272
E-Mail: m.schwab@dkfz.de
The goal of our division is to identify the role
of spontaneous and genetically-related altera-
tions in the development of human cancers.
Our studies are focusing on neuroblastoma, a
common cancer in infants, as well as on differ-
ent types of breast cancer that occur sporadi-
cally or on the basis of an inherited risk.
In addition, we are studying the role of what
are called fragile sites of chromosomes in the
development of genetic alterations associated
with carcinogenesis. We are aiming to identify
genetic changes which may be useful for diag-
nosing or treating cancer or for making predic-
tions about the course of the disease.
In working towards these aims, we are closely
collaborating with clinical partners and us-
ing a modern combination of techniques for
chromosome analysis, the determination of
complex gene expression proles as well as
biochemical and molecular-genetic methods.
Future Outlook:
to develop robust tumor biomarkers by
dening the full repertoire of somatic muta
tions in childhood neuroblastomas and
breast cancer using high-throughput
genomics, particularly whole genome next
generation sequencing. Emphasis will be
placed also on the role of DNA-damage high
risk loci at common fragile sites
to establish clonal evolution models of
primary neuroblastomas, metastasis and
relapsed tumors based on the identied
mutations.
to implement a systems-level understand-
ing of how oncogenic mutations function
ally co-operate during tumor development,
progression and drug resistance
to translate this knowledge into new thera-
peutic concepts of personalised cancer med-
icine by targeting DNA biomarkers from
each individual tumor towards a rational
prediction of combination therapy
ESSENTIAL PUBLICATIONS: (1.) Afanasyeva E. A. et
al. (2011). MicroRNA miR-885-5p targets CDK2 and
MCM5, activates p53 and inhibits proliferation and
survival. Cell Death Differ.,18, 974984. (2.) Afanasye-
va E.A. et al. (2011). CAMTA1, a 1p36 tumor suppressor
candidate, inhibits growth and activates differentia-
tion programs in neuroblastoma cells. Cancer Res., 71,
31423151. (3.) Blumrich A. et al. (2011). The FRA2C com-
mon fragile site maps to the borders of MYCN ampli-
cons in neuroblastoma and is associated with gross
chromosomal rearrangements in different cancers.
Hum Mol Genet., 20, 14881501. (4.) Muth D. et al.
(2010). Transcriptional repression of SKP2 is impaired
in MYCN-amplified neuroblastoma. Cancer Res., 70,
3791-3802.
Six-color FISH detection of a break at the
FRA6F common fragile site. Left, intact
chromosome 6; right, chromosome 6
with a break at FRA6F (arrow)
Biophysics of Macromolecules
Division
Head: Prof. Dr. Jrg Langowski
Gene activity is not determined by the DNA se-
quence alone, but also by its three-dimension-
al organization in the cell: DNA and chromatin
global structure play a crucial role in the regu-
lation of many important biological processes,
such as cell differentiation or cancerogenesis.
The main goal of our research is to study the
three-dimensional structure and dynamics of
the genome in normal and tumor cells and to
describe it by quantitative models. This will
help us understand the connection between
genome structure and normal or pathological
states of the cell. To this aim, we study long-
range interactions in DNA when genes are reg-
ulated by transcription factors, the structure
of nucleosomes and chromatin ber, and the
organization of chromosome territories in the
living cell nucleus. The experiments are sup-
plemented by advanced computer simulation
techniques that describe the organization of
DNA and chromatin as a exible polymer.
Biophysical methods used include in particular
single-molecule techniques (uorescence cor-
relation spectroscopy, single pair FRET, scan-
ning force microscopy), advanced imaging (sin-
gle plane illumination microscopy), light and
neutron scattering, analytical ultracentrifuga-
tion, absorption and uorescence spectrosco-
py, and stopped ow kinetics. We also provide
biophysical methods for the characterization
of other systems of biological macromolecules,
especially in protein-protein and protein-DNA
interaction and intermediate lament proteins.
Future Outlook:
In the future, we shall develop our activities
in the elds of nucleosome and chromatin
dynamics and of intermediate lament (IF)
biophysics. Three major lines of research will
be followed:
1. the role of histone tails and their modi-
cations in chromatin packaging (molecu-
lar epigenetics), using single molecule
FRET as a tool to characterize structural
transitions in nucleosomes;
2. the dynamics of protein transport in the
living cell nucleus, using our newly devel-
oped SPIM microscopy techniques with
ultra-fast detection;
3. the dynamics of assembly of IF proteins
and the biophysical characterization of
their structure and exibility.
We shall continue to build up our computer
simulation activities,ranging from model-
ling biomolecules in atomic detail to coarse-
grained models of the genome architecture in
entire cell nuclei. This theoretical aspect will
always form an important complement to our
experimental research. The ultimate goal is to
design a physical model of the entire cell in
time and space, which can contribute to the
understanding of cancer development and to
its therapy. Our research shall be a step on the
way there.
ESSENTIAL PUBLICATIONS: (1.) Fritsch C. et al. (2011).
Chromosome dynamics, molecular crowding and dif-
fusion in the interphase cell nucleus: A Monte-Car-
lo lattice simulation study. Chromosome Research, 19,
6381. (2.) Bhm V. et al. (2010). Nucleosomal DNA ac-
cessibility governed by the dimer/tetramer interface.
Nucleic Acids Research, 39, 30933102. (3.) Gansen
A. et al. (2009). Nucleosome disassembly interme-
diates characterized by single-molecule FRET. Proc.
Natl. Acad. Sci. USA 11, 1530815313. (4.) Vmosi G. et al.
(2008). Conformation of the c-Fos/c-Jun complex in
vivo: a combined FRET, FCCS, and MD-modeling study.
Biophys J., 94, 28592868.
Biophysics of Macromolecules (B040)
69120 Heidelberg
Tel: +49 6221 42 3390
E-Mail: joerg.langowski@dkfz.de
Mobility map of EGFP-protein in a living HeLa cell
(Source: Dross N, Spriet C, Zwerger M, Mller G,
Waldeck W, Langowski J. (2009) Mapping eGFP
Oligomer Mobility in Living Cell Nuclei. PLoS ONE
4(4): e5041).
Research Program 62
Cancer and other human diseases arise from
genetic aberrations that are either inherited or,
as in most cancers, occur spontaneously in so-
matic cells. These defects cause abnormal ac-
tivities of gene products that lead to malfunc-
tioning of molecular and cellular interactions
which, in consequence, may induce tumors
and cause cancer progression.
The central objective of our division is to un-
derstand the complex molecular mechanisms
that have evolved in the regulation of signal-
ing networks and how these impact on cancer
development, metastasis, and drug resist-
ance. To this end, we generate and maintain
resources for large-scale experimentation,
apply high-throughput functional genom-
ics and proteomics technologies, and analyze
candidate genes using in vitro as well as in vivo
systems. Effects of perturbations (gene gain-
and loss-of-function, miRNA, drugs) imposed
on the signaling processes are experimentally
tested and then computationally modeled.
This generates mechanistic knowledge that
Head: PD Dr. Stefan Wiemann
Elucidating the regulation signaling
network by miRNAs. Breast cancer
cells were transfected with a library
of 810 human miRNA mimics and
induced effects were analyzed by
quantitative analysis of proteins
of the EGFR signaling network.
Thus activating and inhibiting
effects on protein abundance could
be identied (A). This led to the
identication of proteins (blue)
being co-regulated by several
miRNAs (orange), as well as miRNAs
co-regulating several proteins
(B). Activating edges are in red,
inhibiting edges in green.
Molecular Genome Analysis
Division
is exploited to identify new diagnostic and
prognostic markers, as well as to develop novel
strategies for therapeutic intervention.
Similarly, our major focus is on breast cancer,
where we investigate protein and non-protein
factors that are involved in the progression of
different subtypes via their activities in inter-
related signaling networks.
Future Outlook:
We have already seen from our current data
that signaling is not regulated in isolated
pathways, but rather in complex networks.
Therefore, in the future we will investigate
the impact individual perturbations have in a
variety of cellular pathways and at different
levels (DNA, RNA, protein, metabolite, , phe-
notype). This should provide us with a better
understanding of the connectivity in multi-
layer interaction systems. Such information
will be indispensable, for example, to identify
strategies that should help to overcome drug
resistance. While much of our current knowl-
edge is based on in vitro experiments, we need
to validate ndings in vivo in order to prove
their relevance. To this end, we will generate
and test animal models and challenge our hy-
potheses with patient samples. Collaborations
to achieve this have already been established
and promising initial results have already been
obtained.
ESSENTIAL PUBLICATIONS: (1.) Ward A. et al. (2012).
Re-expression of microRNA-375 reverses both ta-
moxifen resistance and accompanying EMT-like
properties in breast cancer. Oncogene:doi:10.1038/
onc.2012.1128. (2.) Uhlmann S. et al. (2012). Global mi-
croRNA level regulation of EGFR-driven cell-cycle pro-
tein network in breast cancer. Mol Syst Biol 8:570. (3.)
Zhang JD. et al. (2011). Time-resolved human kinome
RNAi screen identifies a network regulating mitot-
ic-events as early regulators of cell proliferation. PLoS
ONE 6(7):e22176. (4.) Keklikoglou, I. et al. (2011). Micro-
RNA-520/373 family functions as a tumor suppressor
in estrogen receptor negative breast cancer by tar-
geting NF-kappaB and TGF-beta signaling pathways.
Oncogene:doi:10.1038/onc.2012.1128.
Molecular Genome Analysis (B050)
69120 Heidelberg
Tel: +49 6221 42 4646
E-Mail: s.wiemann@dkfz.de
Molecular Genetics
Division
Head: Prof. Dr. Peter Lichter
Our laboratory applies oncogenomic ap-
proaches for the elucidation of pathomecha-
nisms of tumor etiology and progression and
for the identication of prognostic and predic-
tive genes and gene-signatures. To this end, we
perform large screens by using comprehen-
sive molecular proling technologies revealing
tumor-cell alterations at the level of the ge-
nome, the transcriptome and the epigenome.
Integration of such data sets with clinical data
allows us to identify candidate genes which
are subsequently tested for their i) possible
role in tumor pathomechanisms, ii) potential
as target for novel therapy-strategies, iii) prog-
nostic value to stratify patient subgroups for
risk-adapted therapy regimens and iv) poten-
tial to predict therapy response or resistance
in cancer patients. Major accomplishments of
the last 5 years: We have greatly contributed to
novel tumor sub-classication schemes that
allow stratication of cancer patients for dif-
ferent therapy regimens on the basis of the
genetic tumor proles. We have assessed pre-
dictive gene signatures in a clinical treatment
trial testing neo-adjuvant protocols in breast
cancer. Through the identication of pathogen-
ically relevant genes, we have identied candi-
date targets for the development of novel ther-
apies, in particular in human leukemia, head
and neck tumors, gliomas and colorectal can-
cer. Through the functional characterization of
candidate genes we also developed pre-clinical
models for the testing of novel therapies.
Future Outlook:
One of our major goals is to apply sequenc-
ing of the genomes of cancer cells to identify
the entire spectrum of genetic alterations that
may occur in a given tumor entity and to as-
sess their clinical relevance. This is done with
special focus on pediatric brain tumors, but
also extended to other tumor entities. Further-
more, we wish to implement a strategy for the
establishment of cancer genome sequenc-
ing in a clinical diagnostic setting, following
a three-step procedure: i) sequencing of 50 to
100 candidate genes of oncogenic relevance in
large series of tumors accompanying existing
treatment trials, ii) sequencing of the entire
exome of respective tumor cases, and iii) se-
quencing of whole genomes of selected cases
and assessment of the conditions for whole
genome sequencing in future comprehensive
diagnostic setting. Candidate genes, for which
we have established a pathogenic role in car-
cinogenesis, are currently being tested in pre-
clinical in vitro and in vivo models using known
inhibitors. We plan to complement these stud-
ies by the isolation of novel inhibitors exploit-
ing the DKFZ/EMBL core facility for the screen-
ing of small molecular libraries as well as the
screening of biological extracts through dedi-
cated scientic collaborations. A third focus is
the transfer of biomarkers in gene signatures
into clinical settings through prospective diag-
nostic trials, preferably associated to current
treatment trials.
ESSENTIAL PUBLICATIONS: (1.) Gronych J. et al. (2011).
An activated mutant BRAF kinase domain is suf-
cient to induce pilocytic astrocytoma in mice. J Clin
Invest, 121, 13441348. (2.) Barbus S. et al. (2011). Dif-
ferential retinoic acid signaling in tumors of long-
and short-term glioblastoma survivors. J Natl Cancer
Inst, 103, 598606. (3.) Seiffert M. et al. (2010). Soluble
CD14 is a novel monocyte-derived survival factor for
chronic lymphocytic leukemia cells, which is induced
by CLL cells in vitro, and present at abnormally high
levels in vivo. Blood, 116, 42234230. (4.) Pfister S. et
al. (2008). BRAF gene duplication constitutes a nov-
el mechanism of MAPK pathway activation in low-
grade astrocytomas. J Clin Invest, 118, 17391749.
Molecular Genetics (B060)
69120 Heidelberg
Tel: +49 6221 42 4619
E-Mail: peter.lichter@dkfz.de
Research Program 64
Head: Prof. Dr. Stefan Pfister
Medulloblastoma showing
high level amplications of
MYCN (red signal) and GLI2
(green signal) in different
cells of the same tumor.
Pediatric Neurooncology
Division
Pediatric Neurooncology is currently a vi-
brant eld of research, with countless critical
achievements in recent years in understand-
ing the molecular biology of childhood brain
tumors and translating molecular ndings into
clinical practice. This is desperately needed
from a clinical perspective, since brain tumors
have become the number one cause of cancer-
related mortality in children. Our group aims
to bridge the gap between generating genom-
ic screening data (microarray-based as well as
next-generation sequencing) and exploiting
these data for the sake of our patients. The
rst goal includes the identication, valida-
tion and clinical application of prognostic and
predictive biomarkers in different childhood
brain tumors, including medulloblastoma,
ependymoma, pilocytic astrocytoma and glio-
blastoma. The second major focus involves the
systematic pre-clinical testing of novel smart
drugs, often in combination with established
cytotoxic drugs and/or chemotherapy, to treat
models (in vitro and in vivo), and ultimately
patients, based on the genetic/molecular sig-
nature of the individual tumor (personalized
cancer care).
Pediatric Neurooncology (B062)
69120 Heidelberg
Tel: +49 6221 42 4618
E-Mail: s.pfister@dkfz.de
and Department of Pediatric Hematology and
Oncology, Heidelberg University Hospital
Future Outlook:
The immense biological heterogeneity of child-
hood brain tumors between and within tu-
mors, which is a prerequisite for targeted treat-
ment approaches, is still poorly understood
und thus currently hindering such approaches
on a regular basis in the clinic. To overcome
this shortcoming, we will continue to com-
prehensively investigate the entire genetic
diversity of childhood brain tumors within and
across histopathological entities. A large and
continuously growing repertoire of preclinical
models will allow us to specically test biologi-
cal hypotheseses gained from genome-wide
primary tumor analyses in vitro and in vivo, be-
fore they are recommended for use in patients.
Another focus will be the analysis of clonality
within tumors, their respective metastases,
and tumor relapses, by ultra-deep next-genera-
tion sequencing techniques. This should allow
us to appropriately consider the biological im-
portance of subclones already in the primary
tumor that confer tumor dissemination, local
re-growth, and therapy resistance. As a third
major focus, we have started focusing on the
detection of tumor-specic alteration in body
uids, such as cerebrospinal uid and plasma,
which can be exploited for molecular diagnos-
tics, tumor cell clearance (minimal residual
disease), detection of molecular targets, and
primary resistance mechanisms.
ESSENTIAL PUBLICATIONS: (1.) Witt H. et al. (2011). De-
lineation of two clinically and molecularly distinct
subgroups of posterior fossa ependymoma. Cancer
Cell 20, 143157. (2.) Schwartzentruber J. et al. (2012).
Driver mutations in histone H3.3 and chromatin re-
modelling genes in paediatric glioblastoma. Nature
482, 426431. (3.) Rausch T. et al. (2012). Genome se-
quencing of pediatric medulloblastoma links cata-
strophic DNA rearrangements with TP53 mutations.
Cell 148(1-2), 5971. (4.) Jones D.T. et al. (2012). Dissect-
ing the genomic complexity underlying medulloblas-
toma. Nature, 488, 100105. (5.) Northcott P.A. et al.
(2012). Subgroup-specific structural variation across
1,000 medulloblastoma genomes. Nature, 488, 4956.
Functional Genome Analysis
Division
Head: Dr. Jrg D. Hoheisel
Protein prole of urine samples from
cancer patients and healthy donors.
Samples are depicted as squares
coloured according to disease-state
and gender; black spots represent
proteins that contribute to the
diagnosis. As can be seen from the
plot, discrimination between cancer
and healthy is nearly as good as
discrimination between men and
women.
Research at the Division of Functional Genome
Analysis focuses on the development and im-
mediate application of new technologies for
analysis, assessment and description of both
the realisation and regulation of cellular func-
tion from genetic information. Analysis of
tumour material is the prime focus, with a par-
ticular emphasis on pancreatic cancer. Parallel
studies on an international scale are under
way, for example, on the epigenetic modula-
tion of gene promoters, variations in transcrip-
tion factor binding, changes at transcript levels
of coding and non-coding RNAs, differences in
the actual protein expression and the occur-
rence and ratio of protein isoforms, as well as
the intensity of protein interactions. From the
resulting data, we strive to understand cellular
regulation and its biological consequences. In
combination with clinical data, this knowledge
is used for the creation of a means of reliable,
possibly early and non-invasive diagnosis, ac-
curate prognosis and patient stratication,
monitoring of treatment results and the estab-
lishment of new therapeutic approaches.
As a consequence of the immense amount of
information available at the level of nucleic ac-
ids, developments and applications in the eld
of afnity-based analysis of the proteome have
become a technology focus, since technologi-
cal and analytical processes in this area are still
inadequate for many, in particular biomedical,
purposes.
Future Outlook:
A more recent line of work aims at in vitro im-
plementation of complex biological processes.
Our goal is utilisation in the area of synthetic
biology for the production of molecules and
the establishment of articial molecular sys-
tems. Cell-free biosynthetic production will be
critical for many biotechnological and pharma-
cochemical challenges ahead. Articial experi-
mental systems, on the other hand, will com-
plement current systems biology, evaluating
biological models experimentally. Similar to
physics, insight into cellular functioning will be
gained by an iterative processing of informa-
tion by experimental and theoretical systems
biology. Eventually, this may lead to the estab-
lishment of a fully synthetic self-replicating
system and, ultimately, an archetypical model
of a cell.
ESSENTIAL PUBLICATIONS: (1.) Bttcher M. et al.
(2010). Decoding pooled RNAi screens by means
of barcode tiling arrays. BMC Genomics, 11, 7. (2.)
Schrder C. et al. (2010). Dual-color proteomic prol-
ing of complex samples with a microarray of 810 can-
cer-specic antibodies. Mol. Cell. Prot., 9, 12711280.
(3.) de Souza Rocha Simonini P. et al.(2010). Epigenet-
ically de-regulated microRNA-375 activates Estrogen
Receptor alpha activity in breast cancer. Cancer Res.,
70, 91759184. (4.) Holtrup F. et al. (2011). Nemorosone
specically inhibits growth of pancreatic cancer cells
and induces apoptosis via activation of the unfold-
ed protein response (UPR). Brit. J. Pharmacol., 162,
10451059.
Functional Genome Analysis (B070)
69120 Heidelberg
Tel: +49 6221 42 4680
E-Mail: j.hoheisel@dkfz.de
Research Program 66
With the advent of next-generation sequenc-
ing technologies, it is currently feasible to de-
termine the sequence of a human individual
(e.g. a patient suffering from cancer) in a
matter of days. Other complementary tech-
nologies, such as transcriptome, proteome or
metabolome analysis, deliver further huge
volumes of data with a great potential value
for precise diagnostics. Given the enormous
technological advances in data generation, the
integration of these data in order to generate
new insights into complex biological func-
tion is still a major challenge and can only be
achieved with interdisciplinary approaches.
Our division is developing computer-assisted
methods for interpreting complex genomic
and other biological data, as well as methods
for modeling and simulation of biological pro-
cesses. Major activities include the develop-
ment of integrated bioinformatic approaches
for the interpretation and management of
Head: Prof. Dr. Roland Eils
cancer genome and accompanying clinical
data, the application of state-of-the-art tech-
nologies in automated live-cell imaging and
image analysis, experimental and theoretical
systems biology approaches addressing key
cellular mechanisms and their distortions in
cancer cells, as well as the development of new
synthetic biology tools to manipulate cellular
processes.
Future Outlook:
Our overarching aim is the development of
new insights linking alterations in cancer, or
other diseased cells, with biological functions
in order to nd new potential targets for im-
proved diagnostics and treatment. Therefore
we develop integrated platforms combining
bioinformatic data analysis and mathemati-
cal modeling of complex diseases processes.
In the future, these platforms will provide
computer-assisted diagnostics and therapy
decisions tools to support medical doctors in
patient care.
ESSENTIAL PUBLICATIONS: (1.) Jones DTW. et al. (2012).
on behalf of the ICGC PedBrain Tumor Project. Dis-
secting the genomic complexity underlying medul-
loblastoma. Nature, 488, 100105. (2.) Rausch T. et al.
(2012). Genome sequencing of pediatric medulloblas-
toma links catastrophic DNA rearrangements with
TP53 mutations. Cell, 148, 5971. (3.) Hamacher-Brady
A.(2011). Artesunate activates mitochondrial apopto-
sis in breast cancer cells via iron-catalyzed lysosomal
reactive oxygen species production. The Journal of
Biological Chemistry, 286, 65876601. (4.) Neumann,
L. (2010). Dynamics within the CD95 death-inducing
signaling complex decide life and death of cells. Mo-
lecular Systems Biology, 6, 352.
Theoretical Bioinformatics
Division
Theoretical Bioinformatics (B080)
69120 Heidelberg
Tel: +49 6221 42 3600
E-Mail: r.eils@dkfz.de
The division is
integrating systems
biology methods,
automated image
processing, state of the
art light-microscopy,
cell biology and
bioinformatics methods
with a focus on whole-
genome analysis in
order to develop new
insights into complex
biological functions.
The division of Theoretical Systems Biology
pursues multidisciplinary research to under-
stand how biological function emerges from
interacting components molecules within a
cell and cells within an organism. Our work is
essentially collaborative and characterized by a
tight interplay between experimentation, data
analysis and mathematical modeling. We dis-
sect the molecular switches that regulate the
proliferation and differentiation of T lympho-
cytes and thus, orchestrate adaptive immune
responses. The second focus of the division
is on growth-factor signaling and cell-cycle
control. We study the interplay of these pro-
cesses in human tumor models to understand
how therapy resistance arises from synergistic
oncogene action. From both strands of work
common principles at the systems level are
emerging. Our work aims at identifying the
functional behavior of molecular networks in
the cell and at quantifying the control exerted
by individual components to inform novel
therapeutic approaches.
Head: Prof. Dr. Thomas Hfer
Future Outlook:
A key challenge of quantitative biology is to
understand the interplay between molecu-
lar modules such as those controlling the
induction and maintenance of expression of
master transcription factors for cell fate and
genome-wide programs that mediate coordi-
nated cell function.
ESSENTIAL PUBLICATIONS: (1.) Rand U. et al. (2012).
Multi-layered cellular stochasticity and paracrine am-
plication shape the type-I interferon response. Mol.
Syst. Biol., 8, 584. (2.) Luijsterburg M.S. et al. (2010).
Stochastic and reversible assembly of a multiprotein
DNA repair complex ensures accurate target site rec-
ognition and efcient repair. J. Cell Biol. ,189, 445463.
(3.) Busse D. et al. (2010). Competing feedback loops
shape IL-2 signaling between helper and regulatory T
cells in cellular microenvironments. Proc. Natl. Acad.
Sci. USA, 107, 30583063. (4.) Schulz E. et al. (2009).
Sequential polarization and imprinting of T-help-
er type 1 differentiation by interferon- and interleu-
kin-12. Immunity, 30, 678688.
Theoretical Systems Biology
Division
Theoretical Systems Biology (B086)
69120 Heidelberg
Tel: +49 6221 54 51380
E-Mail: t.hoefer@dkfz.de
Tracking of
individual
tumor cells in
the uorescence
microscope.
Research Program 68
Signaling and Functional Genomics
Division
Head: Prof. Dr. Michael Boutros
Cellular signaling systems control many key
decisions during development, stem cell main-
tenance and tumorigenesis. The focus of our
group is on the systematic dissection of signal-
ing pathways to identify novel molecular pro-
cesses and to understand how pathways con-
nect in cellular networks. We use genetic and
genomic approaches for this purpose, but also
study specic processes at the molecular level
to probe underlying mechanisms. We pursue
two main lines of research:
1. Systematic analysis of Wnt signaling in
model organisms and tumor cells. Ca-
nonical and non-canonical Wnt signaling
play key roles during development and
tumorigenesis. Aberrant regulation of
Wnt signaling has been implicated in can-
cer, as exemplied by mutations in APC,
a negative regulator of Wnt signaling.
During the past years, our laboratory has
contributed to the molecular understand-
ing of Wnt signaling by identifying novel
components and by the characterization
of Wnt-ligand specic cargo receptors.
2. Systems genetics and synthetic lethality.
Genetics underlying many phenotypes,
including most common diseases, are
complex with contributions from multiple
loci. The analysis of synthetic genetic in-
teraction networks reveals how biological
systems achieve a high level of complexity
with a limited repertoire of components.
We have established high-thoughput
methodologies to measure synthetic ge-
netic interaction in model organisms and
cancer cells by RNAi.
Future Outlook:
We are interested in the systematic analysis of
synthetic genetic interactions to dissect geno-
type-phenotype relationships, with a particular
focus on combinatorial mapping approaches
using RNAi and small molecules. Interactions
between genetic variants may be one impor-
tant explanation for the missing heritability
in genome-wide association studies. Extensive
interactions between different genetic alleles
with large effects on many phenotypes have
been documented in many model systems.
We will use quantitative phenotyping by high-
throughput microscopy to measure synthetic
genetic interactions. Genetic interaction data
will be used to model cellular networks with a
particular focus on oncogenic signaling path-
ways. We will also develop novel technologies
required for miniaturization of cellular assays
and high-throughput imaging, for reproducible
cell-based RNAi in primary cell types and novel
approaches to data integration. A second area
of interest is the in-depth analysis of Wnt and
interacting signaling networks in development,
stem and tumor cells. We use a spectrum of
model systems, from Drosophila to mouse and
human cancer cells to identify key components
and understand how they are embedded into
physiological processes. For more information,
visit us at www.dkfz.de/signaling
ESSENTIAL PUBLICATIONS: (1.) Horn T. et al. (2011).
Mapping of signaling networks through synthet-
ic genetic interaction analysis by RNAi. Nature Meth-
ods, 8, 341346. (2.) Fuchs F. et al. (2010). Clustering
phenotype populations by genome-wide RNAi and
multiparametric imaging. Molecular Systems Biolo-
gy, 6, 370. (3.) Boutros M. & Ahringer J. (2008). The art
and design of genetic screens: RNA interference. Na-
ture Reviews Genetics 9: 554566. (4.) Bartscherer, K.,
Pelte, N., Ingelnger, D., & Boutros M. (2006). Secre-
tion of Wnt ligands requires Evi, a conserved trans-
membrane protein. Cell, 125, 52333.
Signaling and Functional Genomics (B110)
69120 Heidelberg
Tel: +49 6221 42 1951
E-Mail: m.boutros@dkfz.de
By silencing genes using RNAi we can
analyse the genes effect in a quantitative
and high-throughput manner. In this
microscopy image of human cancer cells,
nuclei are shown in red, cell membranes in
green, and the cellular scaffolding in blue.
Research Program 70
When cancer cells prolifer-
ate to form a tumor, they
need to grow and to divide.
Regulation of cell division
(i.e. the cell cycle) has been
extensively studied. In com-
parison, the mechanisms
regulating cell growth (i.e.
the accumulation of cell
mass) are less well under-
stood. The Teleman lab
studies cell growth and its
regulation.
For cells to grow, they need
to produce biosynthetic
building blocks such as
nucleotides, amino acids
and lipids. This occurs via
regulation of the metabolic
pathways that produce these molecules. Con-
sequently understanding cell growth requires
understanding metabolism. Cells decide to
grow, however, based on information coming
from outside the cell, such as the presence of
nutrients and growth factors. Cells receive and
process this information via signaling path-
ways such as the insulin pathway. Consequent-
ly understanding cell growth also requires
understanding signaling pathways. Finally, the
signaling pathways regulate the metabolic
pathways, therefore the lab also studies the
interface between signaling and metabolism.
Both the metabolic pathways, as well as the
signaling pathways, are complex and intri-
cate networks. These pathways, however, are
conserved amongst animals. The Teleman lab
studies these pathways using a combination of
human tissue culture together with the fruity
Drosophila, since Drosophila is simplied and
genetically tractable compared to mammals.
Head: Dr. Aurelio Teleman
Future Outlook:
The aim of our work is to understand the
processes regulating cell growth so that this
knowledge can be used in the future for cancer
therapy. Unlike other cells in the body, cancer
cells have mutations that promote cell growth.
Blocking this process will hopefully be a pow-
erful method to specically and efciently in-
hibit tumor progression.
ESSENTIAL PUBLICATIONS: (1.) Xu X. et al. (2012). Insu-
lin signaling regulates fatty acid catabolism at the
level of CoA activation. PLoS Genetics, 8(1):e1002478.
(2.) Pallares C. et al. (2012). Tissue-specific coupling
between insulin/IGF and TORC1 signaling via PRAS40
in Drosophila. Developmental Cell, 22, 172182. (3.)
Hahn K. et al. (2010). PP2A regulatory subunit PP2A-
B counteracts S6K phosphorylation. Cell Metabo-
lism, 11, 438444. (4.) Francis V. et al. (2010). dDOR is
an ecdysone receptor coactivator that forms a feed-
forward loop connecting insulin and ecdysone sign-
aling. Current Biology, 20, 17991808.
Signal Transduction in Cancer and Metabolism
Division
Signal Transduction in Cancer and Metabolism
(B140)
69120 Heidelberg
Tel: +49 6221 42 1620
E-Mail: a.teleman@dkfz.de
Location of adipose tissue
in an adult y revealed by
GFP expression.
Molecular RNA Biology and Cancer
Head: Dr. Sven Diederichs
Our research focuses on the function and
regulation of non-protein-coding RNAs.
MicroRNA biogenesis and its regulatory
steps are elucidated. Long ncRNAs in
lung, liver and breast cancer (e.g. MALAT1,
LUCAIR) are analyzed at the cellular and
molecular level with innovative techniques
(e.g. Genome Editing, RNA Afnity
Purication).
Recent insights into RNA biology induced a
paradigm shift towards the recognition of
RNAs as functionally important molecules
beyond serving as messengers for protein-
encoding genes. A large fraction of the human
genome is transcribed into RNA (up to 70%),
while only 2% are protein-encoding. Non-pro-
tein-coding RNAs execute important functions
in the cell. Very short non-coding RNAs, the
microRNAs, play important roles in gene regu-
lation. The tumor-suppressive or oncogenic
role of many microRNAs and their frequent
deregulation in tumors allow a rst glimpse of
the striking role that non-coding RNAs could
play in cancer. Novel long non-coding RNAs
(ncRNA, lncRNA, lincRNA) fulll important
functions in epigenetic regulation, chromatin
remodeling or splicing. Taken together, the hu-
man cell contains many more RNAs than previ-
ously anticipated and many of them might just
await their discovery as functionally important
molecules in cancer.
Our research focuses on two classes of non-
coding RNAs:
1. microRNAs are short RNAs which regulate
the expression of specic target genes.
We elucidate the microRNA biogenesis
pathway as well as regulatory steps there-
in including the regulation of microRNA
biogenesis factors.
2. As a new and innovative research area, we
analyze long non-coding RNAs and their
role in cancer. After proling the expres-
sion of thousands of ncRNAs in three
tumor entities, we elucidate the cellular
and molecular functions of differentially
regulated ncRNAs in cancer.
Future Outlook:
microRNAs are short, single-stranded RNA
molecules which regulate the expression of
specic target genes. In complex with Argo-
naute proteins (RISC = RNA Induced Silencing
Complex), microRNAs bind to complementary
mRNAs and lead to their degradation, destabi-
lization or blocking of translation and hence in-
hibit the expression of the targeted gene. The
microRNA expression proles in
tumors are frequently altered, thus inducing or
reducing respectively expression of their target
gene. If the target gene is an oncogene and
the microRNA is lost in human tumors, the on-
cogene would be activated and the microRNA
would function as a tumor suppressor gene.
One prominent example for such a pair is the
microRNA let-7 which is downregulated in lung
cancer and targets the well-known oncogene
Ras. Our research group elucidates the mecha-
nisms underlying regulation and processing of
microRNAs and analyses their dysregulation in
human tumors. One focus is the regulation of
microRNA stability, the selection of the micro-
RNA guide strand as well as the function and
regulation of the Argonaute proteins.
As a new thriving research area, we analyze
long non-coding RNAs (ncRNA) and their role
in cancer. After proling the expression of
thousands of ncRNAs in three tumor entities
lung, liver and breast cancer we now elu-
cidate the cellular and molecular function of
differentially regulated ncRNAs in cancer using
innovative techniques like Zinc Finger Nucle-
ases and RNA Afnity Purication.
ESSENTIAL PUBLICATIONS: (1.) Gutschner T. et al.
(2011). Non-coding RNA gene silencing through
genomic integration of RNA destabilizing elements
using zinc nger nucleases. Genome Res., 21, 1944
1954. (2.) Winter J. et al. (2009). Many roads to matu-
rity: microRNA Biogenesis pathways and their reg-
ulation. Nat. Cell Biol., 11, 228234. (3.) Diederichs S.
et al. (2008). Coexpression of Argonaute-2 enhanc-
es RNA interference toward perfect match binding
sites. Proc. Natl Acad. Sci. U.S.A., 105, 92849289. (4.)
Diederichs S. & Haber D.A. (2007). Dual role for Argo-
nautes in microRNA processing and posttranscrip-
tional regulation of microRNA expression. Cell, 131,
1097-1108.
Molecular RNA Biology and Cancer (B150)
69120 Heidelberg
Tel: +49 6221 42 4380
E-Mail: s.diederichs@dkfz.de
Research Program 72
Head: Dr. Ana Garca-Sez
Membrane Biophysics (B160)
BIOQUANT
69120 Heidelberg
Tel: +49 6221 54 51234
E-Mail: a.garcia@dkfz.de
Membrane Biophysics
Our research is focused on the study of dynamic
membrane processes from a quantitative point
of view. We have a special interest in the mito-
chondrial membrane alterations during apop-
tosis and the mechanism of action of the Bcl-2
proteins. To address these problems, we make
use of our expertise in membrane biophys-
ics, advanced microscopy and single molecule
techniques. The proteins of the Bcl-2 family are
essential regulators of apoptosis. They control
a key event in apoptosis: the permeabilization
of the mitochondrial outer membrane (MOM)
that leads to the activation of caspases and to
cell death. Because the Bcl-2 proteins have an
important role in the formation of tumors and
in the cellular responses to anti-cancer thera-
pies, understanding the molecular details of
their action is of great therapeutic interest. We
apply uorescence correlation spectroscopy,
atomic force microscopy and single particle
tracking to in vitro reconstituted systems in
order to characterize the complex interaction
networks between the members of the Bcl-2
proteins. Our strategy includes approaches
to clarify the role of the mitochondrial mem-
brane, which strongly inuences the molecular
mechanism of these proteins. Our desire is to
use the quantitative insight provided by ad-
vanced microscopy and single molecule tech-
niques to build a mathematical model for the
mitochondrial pathway of apoptosis that helps
rening therapeutic approaches.
Furure Outlook:
Our goal is to provide quantitative understand-
ing of the regulation of apoptosis by the Bcl-2
family. To this end, we plan to quantify the
Bcl-2 interactome and to obtain a quantitative
description of the temporal and spatial pro-
gress of apoptosis signalling in mitochondria.
This is not only important to understand the
underlying principles of signalling in biological
systems, but will also contribute to the optimi-
zation of targets for the development of drugs
against cancer and other apoptosis-related
diseases. In addition, the proteins of the Bcl-
2 family have been involved in the dynamics
and morphology of mitochondria. In the long
term, we would like to clarify the molecular
mechanisms involved in these processes and
the physico-chemical aspects related with
membrane bending, fusion and division events
that are necessary to maintain a functional
mitochondrial network. Our group is also com-
mited to the establishment of a technological
platform with expertise in several advanced
microscopy methods such as uorescence cor-
relation spectroscopy, single particle tracking
and atomic force microscopy, among other.
We are interested in the optimization of these
methods for the study of processes in biomem-
branes, including the development of uores-
cence correlation spectroscopy techniques ap-
plied to the membranes of organelles in living
cells.
ESSENTIAL PUBLICATIONS: (1) Apellniz B. et al.
(2010). All-or-none vs. graded: single vesicle anal-
ysis evidences lipid composition effects on mem-
brane permeabilization. Biophys J., 99, 36193628.
(2.) Garca-Sez A.J. et al. (2010) Fluorescence correla-
tion spectroscopy for the study of membrane dynam-
ics and organization in giant unilamellar vesicles.
Methods Mol Biol., 606, 493508. (3.) Garca-Sez
A.J. et al. (2009). Membrane promotes tBID interac-
tion with BCL(XL). Nat. Struct. Mol. Biol., 16, 11781185.
(4.) Garca-Sez A.J. et al. (2007). Pore formation by a
Bax-derived peptide: effect on the line tension of the
membrane probed by AFM. Biophys J., 93, 103112.
Model membrane systems observed with microscopy methods.
Head: Dr. Nathan Brady
We are investigating the control and crosstalk
between programmed cell death (PCD) mecha-
nisms of apoptosis, autophagy and necrosis in
pancreatic, breast and brain cancer cells. Apop-
tosis, the most studied PCD mode (Type I), is
activated by either the death receptor or the
mitochondrial pathway. Autophagy is a pro-
cess by which intracellular components are
sequestered by autophagosomes, which then
fuse with and are degraded by lysosomes. In
the cancer cell autophagy can paradoxically
act as either an alternative cell death pathway
(Type II PCD) or as a potent survival response
to stress, e.g. hypoxia and chemotherapies. Al-
though considered a passive cell death, many
pathways are common to necrosis and PCD
modes. In contrast to apoptosis, necrosis is in-
ammatory due to the rupture of the plasma
membrane and the release of specic cytosolic
components. As apoptosis does not gener-
ate an immune response, the strict focus on
apoptosis-inducing therapies may not be fully
productive.
Our research is aimed at revealing how individ-
ual pathway activities and crosstalk between
PCD pathways can be tuned to optimize intrin-
sic and extrinsic pancreatic cancer cell death.
Using high-resolution imaging of high-content
biosensors we quantitatively map activities
and interdependencies of PCD modes. This ap-
proach achieves superior information content
than commonly reported population-averaged
and representative responses. Measured ac-
tivities and dependencies, including protein-
protein interactions, inter and intra-organellar
communication, and bi-directional cell-to-cell
signaling are analyzed using computational
modeling approaches, with the aim of inte-
grating qualitative and quantitative multi-par-
ametric, multivariate datasets. Our overall goal
3D reconstruction of mitochondria
(green), lysosomes (red) and nuclei (grey).
In response to artesunate, lysosomes
cluster asymmetrically at the nucleus.
Pro-death signaling from lysosomes
induces mitochondrial fragmentation
and convert mitochondria into inducers
of cell death via cytochrome c release.
Systems Biology of Cell Death Mechanisms
is to predict and test chemotherapies which
will optimize both initial PCD responses, as
well as promote an immunogenic response to
induce secondary killing of cancer cells by the
immune system.
Furure Outlook:
The group Systems Biology of Cell Death
Mechanisms (B170) is part of the SBCancer
network within the Helmholtz Alliance on
Systems Biology and is located in BioQuant,
Heidelberg Universitys center for quantitative
biology. Furthermore the group is closely coop-
erating with the European Pancreas Center at
Heidelberg University Hospital headed by Prof.
Dr. Markus Wolfgang Bchler.
ESSENTIAL PUBLICATIONS: (1.) Hundeshagen P. et al.
(2011). Concurrent detection of autolysosome forma-
tion and lysosomal degradation by ow cytometry
in a high-content screen for inducers of autophagy.
BMC Biol, 9, 38. (2.) Wild P. et al. (2011). Phosphoryl-
ation of the Autophagy Receptor Optineurin Re-
stricts Salmonella Growth. Science. 333, 228233.
(3.) Hamacher-Brady A. et al. (2011). Artesunate acti-
vates mitochondrial apoptosis in breast cancer cells
via iron-catalyzed lysosomal reactive oxygen species
production. J Biol Chem, 286, 65876601. (4.) Brady
N.R. et al. (2004). Coordinated behavior of mitochon-
dria in both space and time: a reactive oxygen spe-
cies-activated wave of mitochondrial depolarization.
Biophys J, 87, 20222034.
Systems Biology of Cell Death Mechanisms
(B170)
69120 Heidelberg
Tel: +49 6221 54 51322
E-Mail: n.brady@dkfz.de
Research Program 74
One of the essential characteristics of liv-
ing systems is the ability of their molecular
components to self-assemble into functional
structures and to balance their organisation
within the cellular environment through the
mechanism of homeostasis. It is clear that
protein homeostasis, or proteostasis, is closely
coupled to many other biological processes
ranging from the trafcking of molecules to
specic cellular locations to the regulation of
the growth and differentiation of cells. In ad-
dition, only correctly folded proteins have the
ability to remain soluble in crowded biological
environments and to interact selectively with
their natural partners. It is, therefore, not sur-
prising that the failure of proteostasis mecha-
nisms underpins the pathogenesis of common
diseases of old age, most notably, cancer and
neurodegenerative diseases such as Alzhei-
mers and Parkinsons disease. In many such
diseases proteins self-assemble in an aberrant
manner into large molecular aggregates, in-
cluding soluble oligomeric species and amy-
loid brils. Arguably, strategies to ameliorate
misfolding and aggregation will depend on a
detailed understanding of manipulators of the
proteostasis network.
Head: Dr. Thomas Jahn
Future Outlook:
The main interest of our lab is to advance
our understanding of the molecular events
triggered by protein misfolding and the sub-
sequent impact of protein aggregation on cel-
lular integrity. We combine biochemical and
molecular biological studies to tackle ques-
tions such as: What are the characteristics of
aggregated protein species accumulating in
vivo? How are specic species toxic to cells?
Which cellular mechanisms can be modied
to rescue proteostasis? To address these ques-
tions we combine protein engineering with
the wide range of genetic and molecular tech-
niques available in cell culture and Drosophila
melanogaster. We are also very interested in
establishing novel experimental tools, which
include for example the quantitative analysis
of Drosophila models and the in vivo char-
acterisation of protein-protein interactions.
Hopefully, understanding the detailed mo-
lecular processes leading to protein misfolding
will open new routes towards the design and
development of rational treatments for these
debilitating diseases.
ESSENTIAL PUBLICATIONS: (1.) OSullivan et al. (2012).
Reticulon-like-1, the Drosophila orthologue of the
Hereditary Spastic Paraplegia gene reticulon 2, is re-
quired for organization of endoplasmic reticulum
and of distal motor axons. Hum Mol Genet. 21, 3356
3365. (2.) Jahn T.R. et al. (2011). Detection of Early Lo-
comotor Abnormalities in a Drosophila Model of Alz-
heimers Disease by a Three-Dimensional Tracking
System. J. Neuroscience Methods 197, 186189. (3.)
Jahn T.R. et al. (2008). A common -sheet architecture
underlies in vitro and in vivo 2-microglobulin amy-
loid fibrils. J. Biol. Chem., 283, 1727917286. (4.) Jahn
T.R. et al. (2006). Amyloid formation under physiolog-
ical conditions proceeds via a native-like folding in-
termediate. Nature Struct. Mol. Biol., 13, 195201.
This Junior Research Group is generously
supported by the Chica-and-Heinz-Schaller-
Foundation (CHS).
Schematic energy landscape for
protein folding and aggregation
(see Jahn & Radford FEBS
J. 2005). The competition
between unimolecular folding
and aggregate formation is
intricately balanced by the cellular
proteostasis network.
Proteostasis in Neurodegenerative Disease
CHS Junior Research Group (in Cooperation with Heidelberg
University)
Proteostasis in Neurodegenerative Disease
(B180)
CHS Research Group at CellNetworks
Heidelberg University and DKFZ
69120 Heidelberg
Tel: +49 6221 42-1551
E-Mail: t.jahn@dkfz.de
Lysosomal Systems Biology
Head: Dr. Anne Hamacher-Brady
Lysosomal Systems Biology (B190)
BMBF e:Bio Junior Research Group
BIOQUANT
69120 Heidelberg
Tel.: +49 6221 54 51357
E-Mail: a.brady@dkfz.de
Programmed cell death (PCD) is regulated by
the spatially- and temporally- co-ordinated
interplay of genetically dened signaling path-
ways. The understanding of PCD is of central
importance, in that its successful execution is
the key to cancer therapy. As fundamental dis-
coveries concerning PCD mechanisms, or even
new modes of PCD, are still being reported,
addressing the complexity of PCD signaling
is a growing challenge. Systems biology of-
fers tools to utilize such biological complexity,
through full data integration and mathemati-
cally-derived non-intuitive hypothesis genera-
tion. Intriguingly, PCD undergoes substantial
positive and negative regulation by the endo-
lysosomal compartment.
Future Outlook:
This junior research group is dedicated to the
elucidation of lysosomal control of PCD in can-
cer versus non-cancer cells, with an emphasis
on the cell culture experiments-based genera-
tion of theoretical model predictions, and test-
ing of the in vivo-functionality in the model
organism C. elegans. To that end, we are inte-
grating quantitative uorescence microscopy
and biochemical methods with systems bio-
logical modeling approaches, and are translat-
ing the achieved results to the organism level.
Primary goals are the systemic identication of
regulatory mechanisms governing lysosomal
and PCD signaling pathways and conrma-
tion of in vivo functionality. Our research will
yield insights into specic mechanisms for op-
timizing cancer cell death. This junior research
group is funded by the Federal Ministry of Edu-
cation and Research (BMBF).
ESSENTIAL PUBLICATIONS: (1.) Zhai Z. et al. (2012). An-
tagonistic regulation of differentiation and apopto-
sis by the Cut transcription factor represents a tumor
suppressing mechanism in Drosophila. PLoS Genet.,
8(3):e1002582 (2.) Hamacher-Brady A. et al. (2011). Ar-
tesunate activates mitochondrial apoptosis in breast
cancer cells via iron-catalysed lysosomal reactive ox-
ygen species production. J Biol Chem., 285,65876601.
(3.) Hamacher-Brady A. et al. (2007). Response to my-
ocardial ischemia/reperfusion injury involves Bnip3
and autophagy. Cell Death Differ., 14, 146157. (4.) Ha-
macher-Brady A. et al. (2006). Enhancing macroauto-
phagy protects against ischemia/reperfusion injury
in cardiac myocytes. J Biol Chem., 281, 2977629787.
Metabolic stress-induced,
E3 ligase-mediated
mitochondrial K63
ubiquitin chaining in
breast cancer cells. In
this image mitochondria
are labeled in red, K63
ubiquitin chains in green,
E3 ligase in blue.
Cancer Risk Factors
and Prevention
About 210,000 people in Germany die of cancer each year. 470,000
new cancer cases are diagnosed yearly. Signicant progress in pre-
vention, diagnosis, and treatment of cancer has been made possible
through recent research results in the eld of molecular biology.
Our research program is concerned with identifying risk factors
(primary prevention), early detection (screening), and approaches to
prevent disease progression (chemoprevention). The German Cancer
Research Center occupies a leading position in the area of epidemio-
logical studies as well as in nutrition sciences, biostatistics, and the
application of biomarkers (characteristic biological features that are
key for the prognosis or diagnosis of cancer). We expect that it may
be possible to prevent up to 30 percent of new cancer cases within
the next 20 to 30 years. To reach this goal, the main activities of the
research program are focused on:
integrating laboratory research, epidemiology, and clinical
studies
compiling and extending collections of biological samples and
databases
integrating genome, proteome, and biomarker research into
epidemiological and clinical studies on the causes and preven-
tion of cancer
studies to identify causal connections such as between diet
and cancer
educational measures
research and quality control related to tests and early detection
programs
research in the elds of biostatistics and methodological con-
sulting
Coordinator
Prof. Dr. Kari Hemminki
76 Research Program
Research Program 78
Aberrant DNA methylation is an early event
in tumorigenesis and a major contributor in
the development of solid tumors as well as
leukemias. As an epigenetic alteration, DNA
methylation does not change the sequence of
a gene and thus offers the exciting possibil-
ity for therapeutic removal of the methylation
group by demethylating drugs. Deregulation
of mechanisms that control the establishment
of normal DNA methylation patterns leads to
both extensive aberrant hypo- and hypermeth-
ylation and has been described for several hu-
man malignancies. Global DNA hypomethyla-
tion in human cancers was one of the earliest
changes associated with tumor progression.
Our group has shown that human malignan-
cies are characterized by extensive promoter
CpG island methylation with non-random and
tumor-type specic patterns. It is currently
unknown how tumors acquire aberrant DNA
methylation patterns. Our division is inter-
ested in the molecular mechanisms underlying
the initiation and progression of malignant
cell growth. In particular, we are focusing our
attention on the contribution of epigenetic
alterations in this process and to determine
how epigenetic and genetic alterations cooper-
ate during tumorigenesis. In our studies we are
utilizing current state-of-the-art high through-
put epigenomic assays (e.g. Methylation arrays,
Next generation sequencing and MassAR-
RAY) on clinical samples, cell culture models or
mouse tumor models.
Head: Prof. Dr. Christoph Plass
Future Outlook:
Epigenetics is a fast evolving eld with links to
many research directions in cancer research. A
challenge here will be to integrate epigenetic
questions with other data sets. For example,
the proling of cancer genomes relied heavily
in the past on the description of genetic altera-
tions. Now epigenetic datasets will need to be
integrated in order to completely understand
the molecular defects in cancer. Our division
will focus on four major research directions:
Evaluation of genome-wide epigenetic
patterns in tumor genomes
Identication of novel cancer genes and
pathways targeted by epigenetic altera-
tions
Determining the role of epigenetics in
cancer risk and progression
Evaluate the role of epigenetics in the
regulation of DNA repair
ESSENTIAL PUBLICATIONS: (1.) Raval A. et al. (2007).
Downregulation of death-associated protein ki-
nase 1 (DAPK1) in chronic lymphocytic leukemia.
Cell, 129, 879890. (2.) Chen S.S. et al. (2009). Epige-
netic changes during disease progression in a mu-
rine model of human chronic lymphocytic leukemia.
Proc. Natl. Acad. Sci., 106, 1343313438. (3.) Claus R. et
al. (2012). Quantitative analyses of DAPK1 methyla-
tion in AML and MDS. International Journal of Cancer.
131, E138-42. (4.) Faryna M. et al. (2012). Genome-wide
methylation screen in low-grade breast cancer iden-
tifies novel epigenetically altered genes as poten-
tial biomarkers for tumor diagnosis. FASEB J. [Epub
ahead of print].

DAPK1 Mass Array
Epigenomics and Cancer Risk Factors
Division
Epigenomics and Cancer Risk Factors (C010)
69120 Heidelberg
Tel: +49 6221 42 3300
E-Mail: c.plass@dkfz.de
Cancer Epidemiology
Division
Head: Prof. Dr. Rudolf Kaaks
Our division studies the causes of cancer in
population groups with the aim of identifying
and, if possible, avoiding risk factors so as to
prevent cancer. Our key focus is on the quanti-
cation of risks associated with lifestyle, nutri-
tion and metabolism. In addition, we address
the question of how lifestyle may interact with
genetic susceptibility factors in cancer devel-
opment.
On the basis of established, genetic and non-
genetic risk factors, we build quantitative risk
models for the identication of individuals
who have an increased risk of developing can-
cer compared to others, and who may have
increased benet from targeted prevention
measures, such as regular cancer screening.
A further focus is exploring new routes for pre-
vention and early diagnosis of cancer, as well
as quality control of introduced measures. Due
to the population-related approach, statistical
methods and their further development are of
particularly high relevance in epidemiology.
A major part of our research takes place within
the setting of large-scale prospective cohort
studies, such as the European Prospective In-
vestigation into Cancer and Nutrition (EPIC),
and the Scandinavian Consortium of Maternity
Cohorts. For future studies, our division has a
central role in the development and set-up of
the National Cohort a new, large-scale pro-
spective cohort study in Germany.
Cancer Epidemiology (C020)
69120 Heidelberg
Tel: +49 6221 42 2200
Fax: +49 6221 42 2203
E-Mail: r.kaaks@dkfz.de
ESSENTIAL PUBLICATIONS: (1.) Hsing A. et al. (2012),
Prediction of breast cancer risk by genetic risk fac-
tors, overall and by hormone receptor status. J Med
Genet. 49, 601608. (2.) Ritte R. et al. (2012). Adiposity,
hormone replacement therapy use and breast can-
cer risk by age and hormone receptor status: a large
prospective cohort study. Breast Cancer Res., 14, R76.
(3.) Grote V.A. et al. (2011). Diabetes mellitus, glycated
haemoglobin and C-peptide levels in relation to pan-
creatic cancer risk: a study within the European Pro-
spective Investigation into Cancer and Nutrition (EP-
IC) cohort. Diabetologia, 54, 30373046. (4.) Campa D.
et al. (2011). Genetic variability of the mTOR pathway
and prostate cancer risk in the European Prospective
Investigation on Cancer (EPIC). PLoS One, 6, e16914.
Research Program 80
For common cancers, such as breast, prostate,
colorectal and lung cancers, familial risk for a
person who has an affected family member is
typically around 2.0; approximately 5 to 20%
of cases are familial when two generations
are considered. Known susceptibility genes
are estimated to explain some 15 to 30% of
the familial clustering of breast, prostate and
colorectal cancers but only about 1% of the
familial clustering of lung cancer. The recently
identied low-penetrance genes/loci explain
a large proportion of cancer occurrence (pop-
ulation-attributable fraction) but explain only
a small proportion of the known familial risks
for these cancers. This apparent paradox is ex-
plained by the high allele frequency of the loci
and the low conferred risk. However, the true
functional gene variants may be much rarer
and their contribution to familial risk would
be higher. For many relatively common can-
cers, such as bladder cancer and non-Hodgkin
lymphoma, only low-penetrance genes are
known, and they have negligible contribution
to the familial risk. Thus, there are large gaps
in knowledge on the genetic basis of familial
cancer that the Molecular Genetic Epidemiol-
ogy division is addressing on two fronts. It is
using the worlds largest family dataset, the
Swedish Family-Cancer Database to assess
familial cluster in all cancers. It is character-
izing gene underlying susceptibility to cancer
through genetic association studies, increas-
ingly using genome-wide approaches.
Future Outlook:
The Swedish Family Cancer Database includes
increasingly older generations whereby case
numbers increase and it is possible to study
familial risks in rare and histology-specic
cancers. As one example, familial clustering
of cancer of unknown primary site is offering
interesting insights into metastatic pheno-
type. The database is being used to analyze
age-group-specic familial risks, which will be
turned into user-friendly algorithms for clinical
genetic counseling of cancer patients and their
Head: Prof. Dr. Kari Hemminki
relatives. In due course, the aim is to develop
software packages that would provide relative
and absolute risk estimates for a given fam-
ily structure, age of onset of the diagnosed
cancers, presentation of related tumors and
other relevant data. There are several ongoing
genome-wide association studies, for example
on myeloma, Hodgkin disease, childhood leu-
kemia, for which new low-penetrance genes
have been described. There is a future interest
to associate the ndings with clinical param-
eters, such as survival and response to therapy.
Genome-wide association studies have been
conducted on breast cancer and melanoma
with a special reference to survival. In col-
laborative association studies on breast and
colorectal cancers genetics of cancer prognosis
and gene-environment interactions are under
focus.
ESSENTIAL PUBLICATIONS: (1.) Prasad R. et al. (2010).
Verication of the susceptibility loci on 7p12.2,
10q21.2 and 14q11.2 in childhood precursor B-cell
acute lymphoblastic leukemia. Blood ,15, 17651767.
(2.) Enciso-Mora V. et al. (2010). A genome-wide asso-
ciation study of Hodgkin Lymphoma identies new
susceptibility loci at 2p16.1 (REL), 8q24.21, and 10p14
(GATA3). Nature Genet., 42, 11261130. (3.) Hemmin-
ki K. et al. (2011). Familial risks in cancer of unknown
primary: tracking the primary sites. J Clin Oncol., 29,
435440. (4.) Hemminki K. et al. (2011). Familial mor-
tality and familial incidence in cancer. J Clin Oncol.,
29, 712718.
Genome-wide association study
(Manhattan plot) on Hodgkin
lymphone (Enciso-Mora et al. Nature
Genet 2010). The strongest association
with many SNPs is shown for the MHC
complex on chromosome 6.
Molecular Genetic Epidemiology
Division
Molecular Genetic Epidemiology (C050)
69120 Heidelberg
Tel: +49 6221 42 1800
E-Mail: k.hemminki@dkfz.de
Biostatistics
Division
Head: Prof. Dr. Annette Kopp-Schneider
The main tasks of the Biostatistics Division are
service and research in the eld of biostatisti-
cal methods and their application in cancer
research. We provide statistical support for all
scientic activities of the DKFZ from in vitro
and animal studies to human subject research
including clinical trial, linking methodical
research and biomedical disciplines. Our sup-
port covers experimental design, sample size
estimation, data analysis and preparation of
results for publication. It ranges from brief sta-
tistical consultations to long-term collabora-
tions and covers standard statistical analysis
approaches as well as the development of
complex statistical methods tailored to spe-
cic questions. The ongoing evolution of novel
measurement techniques and platforms and
the development of new research questions
make it necessary to continuously rene the
biostatistical and biomathematical methodol-
ogy and to develop and implement new meth-
ods for analysis. Our current research areas re-
ect the requests we are confronted with from
collaborators. We develop and assess efcient
and valid methods for visualizing, integrating
and analyzing data, in particular high-dimen-
sional molecular data. We develop optimized
biometrical designs in experimental cancer re-
search and in clinical studies. We devise meth-
ods of quantitative risk assessment.
Future Outlook:
One focus of interest of our research is the
evaluation of molecular data in biomarker
studies. We will extend our research to nd
associations with clinico-pathological factors,
prognosis or response to therapy with the aim
to identify diagnostic, prognostic or predictive
factors. We will develop and validate statisti-
cal methods for classication and prediction
using low- and high-dimensional data. The
development of methods for data integration
is becoming an important aspect of our work,
e.g. the development of Bayesian hierarchi-
cal models for classication and prediction,
which can make use of multiple data sources,
while properly accounting for biological inter-
relations between these data. Another area of
research is the development and application of
statistical and stochastic models for dose-re-
sponse relationships. In this context, we inves-
tigate non-linear regression models. A special
focus lies on the description of cellular pro-
cesses using stochastic models to understand
the process of carcinogenesis or the effect of
toxic compounds on cell systems.
ESSENTIAL PUBLICATIONS: (1.) Remke M. et al. (2011)
FSTL5 is a marker of poor prognosis in non-WNT/non-
SHH medulloblastoma. J Clin Oncol., 29, 38523861.
(2.) Hielscher T. et al. (2010). On the prognostic value
of survival models with application to gene expres-
sion signatures. Statistics in Medicine, 29, 818829.
(3.) Groos J. et al. (2010). Application of a two-pheno-
type color-shift model with heterogeneous growth
to a rat hepatocarcinogenesis experiment. Mathe-
matical Biosciences, 224, 95100. (4.) Schenk B. et al.
(2010). The ReProTect Feasibility Study, a novel com-
prehensive in vitro approach to detect reproductive
toxicants. Reproductive Toxicology, 30, 200218.
Biostatistics (C060)
69120 Heidelberg
Tel: +49 6221 42 2391
E-Mail: kopp@dkfz.de
The Principle of
Statistical Inference
Research Program 82
Clinical Epidemiology and Aging Research
Division
The Clinical Epidemiology and Aging Research
Divisions main areas of research include
clinical cancer epidemiology, epidemiology of
chronic age-related diseases and epidemiologi-
cal methods. In the eld of clinical cancer epi-
demiology, the group conducts large-scale epi-
demiological studies on new avenues of more
effective cancer prevention and early detection,
and on issues of quality of medical care, prog-
nosis and quality of life of cancer patients. Fur-
ther large-scale epidemiological studies focus
on detection of risk factors, risk markers and
prognostic factors of cardiovascular disease,
diabetes mellitus and arthritis, thereby aiming
to explore new avenues of enhanced preven-
tion and management of these common and
strongly age-related diseases. Most of the
Divisions studies are conducted in interdisci-
plinary, often international collaboration with
cancer registries, clinical partners and part-
ners from the basic biological sciences. Apart
from application of the highest methodologi-
cal standards in these studies, a major area of
research conducted in the Division is devoted
to further development and enhancement of
methods in epidemiological research.
Future Outlook:
The Division will expand its research on early
detection and screening for colorectal cancer
to focus on questions of high relevance to the
implementation of early detection programs at
the population level.
Future research in early detection and screen-
ing will also be directed towards other gastro-
intestinal cancers. Due to demographic aging,
along with steadily increasing cancer survival
rates, the number and prevalence of cancer
survivors in the population will continue to
increase. The Division will therefore intensify
its research on additional outcomes, such as
quality of life and the occupational and social
participation of cancer survivors. An area of
increasing interest in aging research will be to
enhance the empirical evidence for preventive
and therapeutic interventions in old age. Epi-
demiological aging research in the Division will
increasingly address integrative and functional
endpoints that have received comparatively
little attention thus far, such as indicators of
multimorbidity and frailty, or indicators of
functional limitations, as these are often more
relevant for the elderly than single medical
diagnoses. The Division will also contribute its
expertise in recruitment and follow-up of pop-
ulation-based cohorts and in the areas of clini-
cal epidemiology, aging research and epidemi-
ological methods to the planning and build-up
of the National Cohort of 200,000 older adults
to be recruited from 2013 on and followed over
many years thereafter.
ESSENTIAL PUBLICATIONS: (1.) Brenner H. et al. (2011).
Protection from colorectal cancer after colonoscopy:
population-based case-control study. Annals of Inter-
nal Medicine, 154, 2230. (2.) Breitling L.P. et al. (2011).
Tobacco smoking-related differential DNA methyl-
ation: 27k discovery and replication. American Jour-
nal of Human Genetics, 88, 450457. (3.) Vossen C.Y.
et al. (2011). Clotting factor gene polymorphisms and
colorectal cancer risk. Journal of Clinical Oncology,
29, 17221727. (4.) Jansen L. et al. (2011). Health-related
quality of life over 10 years after diagnosis of colorec-
tal cancer a population-based study. Journal of Clin-
ical Oncology, 29, 32633269.
Head: Prof. Dr. Hermann Brenner
Clinical Epidemiology and Aging Research
(C070)
69120 Heidelberg
Tel: +49 6221 42 1301
E-Mail: h.brenner@dkfz.de
Study assessing the potential
to enhance stool tests for early
detection of colorectal neoplasms.
The bold line indicates improved
detection of advanced adenomas by
immunochemical fecal occult blood
tests among men using low-dose
aspirin (Brenner et al, JAMA 2010).
One of the groups main research interests in
the past ve years has been the identication
of genetic and epigenetic risk factors for breast
and colorectal cancer. A special focus has been
on familial cancer, because genetic risk factors
are supposed to be enriched in this popula-
tion and the power to detect risk variants
is enlarged in comparison to sporadic study
populations. After accepting the foundation
professorship at the Department of Obstetrics
and Gynaecology in 2008, the groups research
interests have shifted to reveal molecular and
cellular factors (e.g. miRNA proles, methyla-
tion signatures, genetic variants, mutations
and circulating tumor cells (CTCs)) associated
with prognosis and therapeutic response, as
well as to uncover molecular serum mark-
ers, as early detection markers for breast or
colorectal cancer and for the recurrence or
metastasis of breast and colorectal cancer. This
is done in cooperation with Hermann Brenner
and Jenny Chang-Claude (DACHS study), Jenny
Chang-Claude (MARIE study) and Andreas
Schneewei (University Womens Clinic and
NCT).
By developing peptide aptamers against ID
proteins, which are overexpressed in several
solid cancers including breast and ovarian
cancer and have been shown to be associated
with poor prognosis, the group is testing bio-
markers as therapeutic targets. One peptide
aptamer against ID1 and ID3 that the group
has isolated has been shown to counteract the
oncogenic activities of ID1 and ID3 in vitro.
Future Outlook:
The major aims of the group are:
identifying rare intermediate and high
breast cancer risk variants that might
contribute more to familial cancer risk
than previously assumed via capture
techniques and next-generation sequenc-
ing methods, combined with the well
characterized familial breast cancer study
population collected by Christian Sutter
and Claus Bartram from the Institute of
Human Genetics and the German Con-
sortium of Hereditary Breast and Ovarian
Cancer (GC-HBOC). The group will also
evaluate the possibility of inherited epige-
netic markers as cancer risk factors.
using methylation signatures, splice vari-
ants, mutations and miRNAs as prognos-
tic and predictive markers and early de-
tection markers.
identifying genetic germline variants that
alter therapeutic response.
detecting genetic germline variants af-
fecting the target gene, its metabolizing
enzymes, and proteins involved in drug
absorption, transport, metabolism and
excretion that might be associated with
therapeutic response. This project will be
done in cooperation with Andreas Schnee-
wei and Frederik Marm (University Wo-
mens Clinic and NCT).
performing the molecular characteriza-
tion of circulating cancer (stem) cells. The
group has started a collaboration with
Andreas Schneewei (University Wom-
ens Clinic, Heidelberg, and NCT), Andreas
Trumpp (Division Stem Cells and Can-
cer, A010) and has built up a metastatic
breast cancer study (MBSUCH).
ESSENTIAL PUBLICATIONS: (1.) Ghoussaini M. et al.
(2012). Identication of three new loci associat-
ed with breast cancer susceptibility. Nat Genet. 44,
312318. (2.) Wirtenberger M. et al. (2006). Identica-
tion of frequent chromosome copy-number polymor-
phisms by use of high-resolution single-nucleotide-
polymorphism arrays. Am J Hum Genet., 78, 520522.
(3.) Frank B. et al. (2008). Association of a common
AKAP9 variant with breast cancer risk: a collaborative
analysis. J Natl Cancer Inst, 100, 437442. (4.) Stein S.
et al. (2010). Genomic Instability and Myelodyspla-
sia with Monosomy 7 Consequent to EVI1 Activation
after Gene Therapy for Chronic Granulomatous Dis-
ease. Nat Med., 16, 198204.
Molecular Epidemiology
Research Group
Head: Prof. Dr. Barbara Burwinkel
Molecular Epidemiology (C080)
69120 Heidelberg
Tel: +49 6221 42 1461
E-Mail: B.Burwinkel@dkfz.de
12p12.3 deletion identied in two familial CRC
cases using Affymetrix SNP 6.0 array (x axis: logR
intensity ratio, blue bars; y axis: B allele frequency,
red circles). Deletion regions are in black boxes.
Tumor Immunology
The immune system is our bodys most powerful weapon to combat
pathogens and cancer cells. However, tumor cells have a reper-
toire of tricks to evade the immune response. The divisions of the
Research Program Tumor Immunology investigate the mechanisms
regulating the behavior of immune cells. Research work focuses on
cell proliferation and programmed cell death (apoptosis) as well as
on the activation and regulation of immune cells. Also under inves-
tigation are cancers affecting the immune system as such. The aim
is to better understand the role of the immune system in cancer,
AIDS, and autoimmune diseases. The ndings will be translated into
new approaches for clinical application to utilize the potential of
the immune system for ghting cancer.
Coordinator
Prof. Dr. Hans-Reimer Rodewald
84 Research Program
Research Program 86
The immune system is characterized by its ca-
pability to recognize and eliminate malignant
tumors. Immunotherapies exploit this unique
ability and promise to become an efcient
complement to standard tumor treatments
in the future. The objective of the division
Translational Immunology" is to gain new
insights into the immune defence system of
cancerous cells and to evolve the results from
basic research through to clinical treatments.
The pursuit of this is based on close interdis-
ciplinary collaboration with the oncological
departments of the university hospital. New
therapeutic concepts developed by the division
are being translated into clinical application
under the auspices of the National Center for
Tumor Diseases (NCT) Heidelberg. Effective
immune responses are based on a variety of
active principles. The division is looking for op-
tions to draw on the immune systems func-
tions as a complementary treatment in the
battle against cancer within the framework
of synergystic projects. The project T Cell Tu-
mor Immunity" (Prof. Dr. Beckhove) describes
formative and regulative mechanisms of T cell
tumor responses. The project group Tumoran-
tigens (Prof. Dr. Eichmller) investigates the
immunogenicity of tumor-associated antigens
and develops strategies for tumor-specic im-
munization using preclinical model systems.
Future Outlook:
The examination of conditions and activation
of tumorlytic T and NK lymphocytes are the
focus of the project Antigen Presentation and
T Cell Activation" (PD Dr. Momburg). Both pro-
jects are complemented by the construction
of virus-like particles (VLP) aimed to stimulate
immune responses against cancer (project
VLP" , Dr. Cid). In the past decade, monoclonal
antibodies, either on their own or in combina-
tion with chemotherapy, have proven to be an
effective therapeutic agent in the treatment
of different tumor diseases. New therapeutic
antibodies are being developed with the help
of antibody engineering and tested before
Head: Prof. Dr. Philipp Beckhove
their clinical application (project Antibody
Therapy", Dr. Moldenhauer). The role cell adhe-
sion molecules play as target structures for im-
munotherapies related to metastasis and their
role during tumor metastasis are the central
topics of the project Adhesion and Metas-
tasis" (Prof. Altevogt). Particular glycosylation
patterns on tumor cells and tumor vessels are
not only decisive preconditions of tumor an-
giogenesis and tumor progression, but they
also represent ideal target antigens for new
anti-tumor strategies via mimetics with ana-
logue structure and glycan-specic cytotoxic
antibodies (project Glycoimmunology" , PD Dr.
Schwarz-Albiez).
ESSENTIAL PUBLICATIONS: (1.) Ge Y. et al. (2012). Met-
ronomic cyclophosphamide treatment in metasta-
sized breast cancer patients: immunological effects
and clinical outcome. Cancer Immunol Immunother.
61, 353362. (2.) Bonertz A. et al. (2009). Antigen-spe-
cific Tregs control T cell responses against a limited
repertoire of tumor antigens in patients with colo-
rectal carcinoma. J Clin Invest. 11, 33113321. (3.) Dom-
schke C. et al. (2009). Intratumoral cytokines and
tumor cell biology determine spontaneous breast
cancer-specific immune responses and their corre-
lation to prognosis. Cancer Research. 21, 84208428.
(4.) Beckhove P. et al. (2004). Specifically activat-
ed CD45R0+ central and effector memory but not
CD45RA+ nave T cells from bone marrow of cancer
patients selectively home to and reject xenotrans-
planted autologous tumors. J. Clin. Invest. 114, 6776.
Translational Immunology
Division
Tumor Immunology
Translational Immunology (D015)
German Cancer Research Center and NCT
69120 Heidelberg
Tel: +49 6221 56 5466
E-Mail: p.beckhove@dkfz.de
Immunogenetics
Division
Head: Prof. Dr. Peter Krammer
The division of Immunogenetics has made
several groundbreaking contributions to the
eld of programmed cell death (apoptosis).
The group established that the CD95 recep-
tor does not only act as a death receptor that
induces apoptosis, but also triggers the NF-kB
pathway involved in tumor proliferation, inva-
sion and metastasis. Together with APOGENIX,
a company founded with DKFZ, the group has
developed the biological APG101, a soluble fu-
sion protein consisting of two extracellular
domains of the CD95 receptor and an antibody
Fc fragment (CD95-Fc). APG101 has therapeutic
effects in many diseases, e.g. in cancer.
Two TCM anti-cancer compounds, Wogonin
and Rocaglamide could be shown to preferen-
tially induce apoptosis in tumor cells. The cyc-
lin-dependent kinase 9 (CDK9) was identied
as the direct molecular target of Wogonin, and
Prohibitin 1 and 2 were identied as the target
of Rocaglamide. These studies point to the po-
tential use of these compounds as an adjuvant
for anti-cancer therapy. Annexins were shown
to be involved in induction of peripheral toler-
ance against antigens from apoptotic cells.
Members of the annexins protein family are
transferred early upon induction of cell death
to the surface of apoptotic cells. By inhibition
of NF-B signaling, annexins suppress dendrit-
ic cell (DC) maturation.
Finally, a redox-regulating molecule, AF-1, was
identied that is associated with aging of hu-
man cells. Knock down of AF-1 can also sub-
stantially extend stress resistance and life span
in drosophila. AF-1 seems to be involved in a
general aging mechanism.
Future Outlook:
Future work will be directed at trying to block
the CD95 death pathway. In addition, CD95 me-
diated non-death pathways will be addressed
by two approaches: resensitization towards
apoptosis by drugs, and blocking of CD95 re-
ceptor signaling by drugs and/or soluble CD95
receptors. Further trials with the soluble CD95
receptor APG101 are currently planned. The
binding of Wogonin and Rocaglamide to their
targets will be elucidated at the atomic level.
The insight into these molecular interactions
will serve as a platform for further drug screen-
ing. Furthermore, the molecular mechanisms
of novel NF-B regulating phosphatases will
be characterized. Since the enzymes identied
inuence cell death of tumor cells, the ulti-
mate goal is to nd ways to manipulate them
to treat patients. Annexins on the surface of
apoptotic tumor cells suppress the anti-tumor
immune response. Therefore, manipulation
of the annexin system promises benets for
tumor therapy. The group will focus on the
identication of the annexin receptor and
the molecular mechanism by which annexin
treatment inhibits proinammatory signaling.
Future directions of the groups work in redox
regulation will involve the investigation of the
role of AF-1 as a putative master switch in ag-
ing. Here, the focus of the division will be on
AF-1s molecular mechanism, its drugability,
and its role in age-related diseases.
ESSENTIAL PUBLICATIONS: (1.) Baumann S. et al.
(2008). Wogonin preferentially kills malignant lym-
phocytes and suppresses T-cell tumor growth by in-
ducing PLCgamma1- and Ca2+-dependent apopto-
sis. Blood, 111, 23542363. (2.) Brenner D. et al. (2009).
Phosphorylation of CARMA1 by HPK1 is critical for NF-
kappaB activation in T cells. Proc Natl Acad Sci U S
A, 106, 1450814513. (3.) Fricker N. et al. (2010). Mod-
el-based dissection of CD95 signaling dynamics re-
veals both a pro- and antiapoptotic role of c-FLIPL. J
Cell Biol, 190, 377389. (4.) Krammer P. H. (2007). Life
and death in peripheral T cells. Nat Rev Immunol, 7,
532542.
Tumor Immunology
Immunogenetics (D030)
69120 Heidelberg
Tel: +49 6221 42 3718
E-Mail: p.krammer@dkfz.de
CD95 signaling: A death inducing signaling
complex (DISC) assembles upon binding of the
CD95 ligand (CD95L) to its receptor CD95. The
proteins FADD, procaspases-8/10 and c-FLIP
have been shown to be key components of this
structure (for details see Krammer et al. 2007, Nat
Rev Immunol). The signal can either lead to cell
death (apoptosis) or to proliferation and invasion.
Research Program 88
Tumor Immunology
Head: Prof. Dr. Bernd Arnold
Molecular Immunology
Division
Molecular Immunology (D050)
69120 Heidelberg
Tel: +49 6221 42 3731
E-Mail: b.arnold@dkfz.de
of new molecular targets suitable for thera-
peutic reprogramming of the immune system.
Tumor microenvironment: Our studies show
that T cell homing into tumors can be in-
creased by a number of strategies, all of which
result in normalization of the tumor vascu-
lature. Thus, normalization is likely to play a
major role in T cell inltration, which is a pre-
requisite for tumor rejection. Therefore, we will
analyze the cellular and molecular mecha-
nisms resulting in modulation of the tumor
microenvironment, vessel normalization, and
T cell inltration. Identication of factors en-
hancing T cell inltration will have important
implications for clinical immunotherapy.
ESSENTIAL PUBLICATIONS: (1.) Garbi N. et al. (2006).
Impaired assembly of the MHC class I peptide load-
ing complex in mice decient for the oxidoreductase
ER60. Nat. Immunol. 7, 93102. (2.) Papatriantafyllou
M. et al. Dickkopf-3, an immune-modulator in periph-
eral CD8 T cell tolerance. Proc Natl Acad Sci USA 109,
16311636 (3.) Hamzah J. et al. (2008). Vascular nor-
malization in RGS5-decient tumors promotes im-
mune destruction. Nature, 453, 410414 (4.) Hoch-
weller K. et al. (2010). Dendritic cells control T cell
tonic signalling required for responsiveness to for-
eign antigen. Proc. Natl. Acad. Sci., 107, 59315936.
The Division of Molecular Immunology investi-
gates basic mechanisms that are important for
immunological tumor rejection with the aim
to exploit this knowledge for the development
of novel immunotherapeutic strategies. Our re-
search groups focus on the following topics:
Antigen presentation: For successful destruc-
tion of tumor cells T lymphocytes need to be
activated by dendritic cells presenting tumor
antigens. Therefore, we are studying homeo-
stasis and stimulatory capacity of dendritic
cells and measure the precise biophysical in-
teraction forces between antigen-presenting
cells and T cells.
Peripheral tolerance: T lymphocytes are often
rendered tolerant by tumors and, therefore,
fail to attack the tumor. By investigating the
molecular pathways leading to tolerance in-
duction we identied a novel immune-modu-
lator, Dickkopf-3, that can down-regulate T cell
responses and may represent a novel tumor
escape mechanism.
Tumor microenvironment: The tumor vascula-
ture can restrict the access of T lymphocytes
into the tumor, thereby preventing tumor
eradication. We succeeded in strongly improv-
ing inltration and tumor rejection by strate-
gies that modulate the tumor microenviron-
ment, including local irradiation, efcient
depletion of regulatory T cells, and targeting of
vasculature-associated genes. These strategies
will be translated into the clinic.
Future Outlook:
The Division of Molecular Immunology will
continue to investigate basic mechanisms that
are crucial for immunological tumor rejection.
We are focusing on the following aims:
Peripheral tolerance: Tissues particularly sen-
sitive to inammatory damage, like the brain
and the eye, create an immune-suppressive
microenvironment to limit immune responses.
Likewise, developing tumors can generate a
tolerogenic milieu, which facilitates tumor pro-
gression and antagonizes the efcacy of vac-
cination strategies. Our understanding of the
key cellular and molecular players responsible
for the induction and mainte-
nance of tolerance is yet to be
completed. Therefore, we will
address the molecular basis of
immune silencing by healthy
organs and tumor cells and
will focus on the identication
We identied Dickkopf 3 as a
novel immune modulator which
is mainly expressed in tissues
termed immune-privileged, such
as brain and eye. It dampens
T cell reactivity in such tissues
protecting them against immune
destruction. Here the expression
of Dickkopf 3 is shown in neurons
in the mouse brain.
Tumor Immunology
Developmental Immunology
Division
Head: Prof. Dr. Bruno Kyewski
Developmental Immunology (D090)
69120 Heidelberg
Tel: +49 6221 42 3734
E-Mail: b.kyewski@dkfz.de
capsule
subcapsular
epithelial cell
cortical
epithelial cell
thymocyte
macrophage
trabecule
medullary
epithelial cell (mTEC)
B-cell
dendritic cell
c
o
r
t
e
x
m
e
d
u
l
l
a
A
Future Outlook:
PGE represents one of the most fascinating
and arcane aspects of T cell tolerance. In future
we will further pursue our studies on the cellu-
lar and molecular regulation of this phenome-
non in experimental in vitro and in vivo models.
In particular, we would like to understand how
a terminally differentiated epithelial cell type
generates such a diverse self-antigen reper-
toire in a mosaic fashion, such that the expres-
sion patterns of individual mTECs faithfully
add up to the full complement of self-antigens
at the population level. In this context we will
search for rules which guide the selection of
promiscuously expressed genes in mTECs at
the single cell and population level. We expect
the different, but complementing, avenues of
inquiry to provide us with a more comprehen-
sive understanding of the functional organiza-
tion of the thymic- microenvironment in the
context of self-tolerance and new insights into
gene (co)-regulation in case of pGE and be-
yond. In addition, we will continue to directly
apply our ndings in basic research to human
disorders, i.e. further explore the interrela-
tionship between pitfalls of pGE and human
autoimmune diseases and identify underlying
molecular mechanisms controlling the intra-
thymic expression of prominent auto-antigens.
Finally, we will exploit our acquired knowledge
on the biology of human thymic epithelial cells
to develop new diagnostic markers for differ-
ent human thymoma subtypes.
The thymus is the site where
central T cell tolerance is imposed.
It consists of an outer cortex and
a central medulla. The medulla
is densely packed with various
antigen-presenting cells, which
present a plethora of self-antigens
to developing T cells and thus
induce self-tolerance. Medullary
thymic epithelial cells (shown in
red) have the unique property to
express numerous tissue-restricted
self-antigens in a promiscuous
fashion and thus are essential for
the prevention of autoimmunity.
Self/non-self discrimination is a hallmark of
the immune system of multi-cellular organ-
isms. The thymus of higher vertebrates plays a
central role in the induction of T cell tolerance
(central tolerance). During self-tolerance
induction, the highly diverse T cell receptor
repertoire is probed against an unknown array
of self-antigens mirroring the immunologi-
cal self of the body. These interactions rid the
repertoire of auto-reactive T cells. Our discov-
ery of promiscuous gene expression (pGE) and
its essential function in preventing organ-
specic autoimmunity has led to a reappraisal
of the role of central tolerance in self/non-self
discrimination. The diversity of self-ligands in
the thymus is to a large extent generated by
ectopic expression of numerous tissue-restrict-
ed antigens in medullary thymic epithelial
cells (mTECs). This gene pool encompasses >
10 % of all known genes and represents virtu-
ally all tissues of the body. Promiscuous gene
expression allows self-antigens, which other-
wise are expressed in a spatially or temporally
restricted manner, to become continuously
accessible to developing T cells thus rendering
them tolerant. Specic failure of promiscuous
gene expression can lead to severe organ-spe-
cic autoimmune diseases like type 1 diabetes
mellitus. This gene pool also includes tumor-
associated antigens, thus imposing immuno-
logical tolerance towards tumors, a fact to be
considered in the selection of tumor antigens
for clinical vaccination trials.
ESSENTIAL PUBLICATIONS: (1.) Giraud M. et al. (2007).
An IRF8-binding promoter variant and AIRE control
CHRNA1 promiscuous expression in thymus. Nature,
448, 934937. (2.) Klein L. et al. (2009). Antigen pres-
entation in the thymus for positive selection and
central tolerance induction. Nat. Rev. Immunol., 9,
833844. (3.) Tykocinski L. O. et al. (2010). Epigenetic
regulation of promiscuous gene expression in thym-
ic medullary epithelial cells. Proc. Natl. Acad. Sci. U
S A, 107, 1942619431. (4.) Lv H. et al. (2011). Impaired
thymic tolerance to alpha-myosin directs autoim-
munity to the heart in mice and humans. J. Clin. In-
vest., 121, 15611573.
Research Program 90
Tumor Immunology
Head: Prof. Dr. Hans-Reimer Rodewald
Cellular Immunology
Division
Cellular Immunology (D110)
69120 Heidelberg
Tel: +49 6221 42 4120
E-Mail: office.rodewald@dkfz.de
The Division of Cellular Immunology is inves-
tigating physiological and pathological pro-
cesses of the development of cells and organs
in the immune system as well as their immu-
nological functions.
We generated reporter knockin mice to dem-
onstrate that T cells and myeloid cells (e.g.
dendritic cells and granulocytes) arise in the
thymus from distinct progenitors under physi-
ological conditions. Moreover, a genetic block
of Notch1 signals in T cell progenitors leads
to their developmental deviation to dendritic
cells instead of T cells. T cell development and
maturation occur in a discrete primary immu-
nological organ, the thymus. Previous projects
focussed on thymus organogenesis while
in current projects we investigate functions
of the transcription factor FoxN1 in thymic
epithelial cells (TECs). A central area of our re-
search is the investigation of the roles of mast
cells in the immune system. Different knock-
out mice enabled us to characterize an enzyme
of the heparin biosynthesis pathway and to
elucidate the mechanism by which mast cell
proteases can degrade endothelin, a blood
pressure regulating factor, and detoxify struc-
turally related snake toxins.
Future Outlook:
Members of our team study the dynamic pro-
cesses of stem cell differentiation and the plas-
ticity of the development of mature immune
cells. To this end, we develop mouse models in
which stem cells and their progeny are induc-
ibly labelled at a certain time point. Further-
more, we have generated universal stem cell
recipient mice which can be transplanted with
bone marrow stem cells without the need for
myeloablation, e.g. by irradiation. In another
fate mapping project we are investigating the
origins of different tissue resident macrophag-
es like osteoclasts, Kupffer cells in the liver, and
microglia in the central nervous system. We
are extending our thymus research towards
unravelling mechanisms of acute T cell leukae-
mia (T-ALL) development. We discovered that
thymocytes undergo transformation if they
non-physiologically persist in the thymus. This
occurs with surprisingly high incidence if the
inux of fresh progenitors into the thymus is
interrupted. We hope that this new T-ALL mod-
el shall enable us to investigate the cellular
and molecular mechanisms of T-ALL formation
in the thymus. Comprehensive investigations
Immunuorescence staining of lymphocytes (red) and
osteoclasts (green) in bone marrow of a mouse femur
of mast cell functions remain a central area of
our research. We have generated a mouse mu-
tant, which is completely mast cell decient
but has an otherwise normal immune system.
This new mouse represents an excellent model
to clarify the question in which infections or
diseases beyond allergy mast cells play im-
munological roles. Specically, we will test the
roles of mast cells in wound healing, asthma,
responses to infections and in tumour models.
ESSENTIAL PUBLICATIONS: (1.) Schlenner S.M. et al.
(2010). Fate mapping reveals separate origins of T
cells and myeloid lineages in the thymus. Immunity,
32, 426436. (2.) Martins VC et al. (2012). Thymus-au-
tonomous T cell development in the absence of pro-
genitor import. J Exp Med 209, 14091417. (3.) Feyer-
abend T.B. et al. (2011). Cre-Mediated Cell Ablation
Contests Mast Cell Contribution in Models of Anti-
body- and T Cell-Mediated Autoimmunity. Immuni-
ty, 35, 832844. (4.) Rodewald H.R. et al. (2012) Wide-
spread immunological functions of mast cells: fact or
fiction? Immunity, 37, 1324
Tumor Immunology
Innate Immunity
Boveri Junior Research Group
Head: PD Dr. Adelheid Cerwenka
Innate Immunity (D080)
69120 Heidelberg
Tel: +49 6221 42 4480
E-Mail: a.cerwenka@dkfz.de
The innate immune response serves as the
rst line of immune defence and does not only
directly lead to tumor cell destruction, but
also to efcient subsequent activation of the
adaptive immune system. The Boveri Junior
Group Innate Immunity" investigates Natu-
ral Killer (NK) cells and myeloid cell subsets
in cancer with the goal to improve therapeu-
tic anti-tumor strategies. NK cells potently
kill tumor cells and produce inammatory
cytokines. Their activation is determined by a
delicate balance between signals delivered by
inhibitory receptors, most of which are specic
for self-MHC class I, and activating receptors.
Many tumors lose expression of MHC class I
molecules and frequently escape from direct
recognition by CD8+ T cells, but become highly
susceptible to NK cell-mediated killing. Thus,
we believe that it is of major importance to
explore NK cell-based therapies against cancer.
Our research focuses on three strategies to
amplify innate immune cell-mediated anti-
tumor responses. 1.) It is our goal to guide high
numbers of highly active, persistent NK cells
to the tumor site. 2.) We attempt to increase
the visibility of tumor cells to NK cells by the
upregulation of ligands for activating NK cell
receptors on tumors. 3.) We aim at exploring
inammatory pathways in myeloid cells and
their functional importance in the context of
cancer.
Future Outlook:
Our future projects will further continue to
develop strategies aiming at harnessing NK
cells against tumors. In addition, candidates in
inammatory signalling pathways in myeloid
cells and their functional importance in the
context of cancer inammation will be investi-
gated. Our overall program is designed to gain
novel insight in mouse and human NK cell and
myeloid cell biology building the basis for in-
novative strategies of immunotherapy against
cancer.
ESSENTIAL PUBLICATIONS: (1.) Ormsby T. et al. (2011).
Btk is a positive regulator in the TREM-1/DAP12 sign-
aling pathway. Blood, 118, 936945 (2.) Wendel M.
et al. (2008). NK cell accumulation in tumors is de-
pendent on IFN-g and CXCR3 ligands, Cancer Res., 68,
84378445. (3.) Nausch N. et al. (2008). Mononuclear
Myeloid-Derived Suppressor Cells express RAE-1
and activate NK cells. Blood, 112, 40804089. (4.) Cer-
wenka A. et al. (2001). NK cells, viruses and cancer.
Nature Immunol. Rev., 1, 4149.
CD56-positive NK cells (brown)
inltrating cervical carcinoma
Research Program 92
Tumor Immunology
Head: Dr. Markus Feuerer
Immune Tolerance
Immune Tolerance (D100)
69120 Heidelberg
Tel: +49 6221 42 1530
E-Mail: m.feuerer@dkfz.de
The immune system has evolved over time to
defeat external threats such as bacteria and
viruses as well as internal threats like cancer.
The ability of the immune system to destroy
such a diverse number of foreign invaders is a
tribute to its exibility. However, this comes at
a price and the complexity can lead to severe
autoimmune diseases. In addition, misguid-
ed or deregulated immune responses have
recently been implicated in non-classical im-
mune disorders such as obesity. To minimize
such collateral damage, powerful mechanisms
of immune tolerance have evolved to keep
unwanted immune responses at bay. These
mechanisms must be tightly controlled as
overactive immune tolerance can specically
counteract desirable immune reactions (e.g.
anti-tumor or anti-microbial). Peripheral im-
mune regulation is maintained by specialized
cells, including T cells and myeloid-derived
cells. The ability to actively suppress an im-
mune response makes regulatory T (Treg) cells
important elements to consider. Treg cells are
a specialized lineage of CD4+ T cells, charac-
terized by expression of the transcriptional
regulator Foxp3. Treg cells are essential for the
maintenance of self-tolerance.
Our goal is to explore Treg cell biology in the
context of autoimmunity and anti-tumor-im-
munity. What are the molecules behind these
specialized cells? In addition, we are interested
in how the local microenvironment shapes the
function of Treg cells.
Future Outlook:
Harnessing the potential of Treg cells is one
of the most promising new immune system
based approaches to control immune function
and treat autoimmune diseases and cancer.
However, future strategies to bring Treg-based
therapies into clinical application will rely on
a better understanding of the molecular path-
ways that control the development and func-
tion of Foxp3+ Treg cells.
Peripheral immune regulation is not only
maintained by adoptive immune cells but also
by innate cells such as myeloid cells. Innate
cells are believed to be the earliest cells acti-
vated and recruited to a site of inammation.
Thus, signals integrated and released by these
early witnesses will crucially inuence the
overall response to the challenge.
As a second main project, we are focusing
on understanding the role that myeloid cells
play in immune regulation. Myeloid cells are a
heterogeneous group of cells involved at the
interface of inammation and wound-healing.
Some members promote inammation where-
as others have suppressive or regulatory func-
tions. We are especially interested in investi-
gating how monocytes and their progenies
(monocyte-derived-DCs and -macrophages)
can contribute to inammation or productive
immunity on one hand and tolerance or tissue
repair on the other. What is their relationship
to inammation that promotes cancer forma-
tion or progression?
ESSENTIAL PUBLICATIONS: (1.) Feuerer M. et al.
(2009). How punctual ablation of Foxp3+ T cells un-
leashes an autoimmune lesion within the pancre-
as islets. Immunity, 31, 654664. (2.) Feuerer M. et
al. (2009). Lean, but not obese, fat is enriched for a
unique population of regulatory T cells that affect
metabolic parameters. Nature Medicine,15, 930939.
(3.) Feuerer M et al. (2003). Bone marrow as a priming
site for T-cell responses to blood-borne antigen. Na-
ture Medicine, 9, 11511157. (4.) Feuerer M. et al. (2001).
Therapy of human tumors in NOD/SCID mice with
patient-derived reactivated memory T cells from
bone marrow. Nature Medicine, 7, 452458.
Structural and Functiona Genomics
Immune cells inltrate and destroy
pancreatic insulin producing islet cells.
Imaging and
Radiooncology
It is the task of the Research Program Imaging and Radiooncology"
to introduce new ndings, methods, and technologies into the dia-
gnosis and treatment of cancer. Our goal is to detect early and com-
prehensively understand the specic tumor biology and to tailor ra-
diooncologic treatment to the individual patient for improving cure
rates and quality of life. Knowledge gained from basic research in
the elds of imaging, radiation physics, engineering, radiopharmacy,
as well as radiation- and tumor biology are translated in systematic
preclinical and clinical studies and nally applied in clinical studies
for improving diagnostic and therapeutic strategies. The multidis-
ciplinary Research Program is centred around the development and
implementation of imaging and radiotherapy technology, which
is achieved through intensive collaboration between the funda-
mental research divisions of the Research Program and the Clinical
Cooperation Units. Based on the complexity of the matter, different
medical specialists are collaborating with scientists of various dis-
ciplines, including physicists, mathematicians, computer scientists,
engineers, chemists and biologists.
Coordinator
Prof. Dr. Heinz-Peter Schlemmer
94 Research Program
Research Program 96
Head: Prof. Dr. Heinz-Peter Schlemmer
Radiology
Division
Radiology (E010)
69120 Heidelberg
Tel: +49 6221 42 2563
E-Mail: h.schlemmer@dkfz.de
The Division of Radiology is developing imag-
ing methods for early detection of cancer and
characterizing their functional and biologic
features, e.g. blood supply, metabolism and
molecular mechanisms. In close coopera-
tion with the other divisions of the research
program Ultrasonography (US), Computed
tomography (CT), Magnetic Resonance Imag-
ing (MRI) and Positron Emission Tomography
Hybrid Imaging Devices (PET/CT and PET/MR)
are advanced and evaluated in patient studies.
For this purpose, up-to-date technologies are
available including ultra-high eld MRI, dual-
energy CT and PET/CT. Methodic developments
has been running over 5 years. Novel tools are
developed to quantify therapy response, e.g.
dual-energy CT for assessing changes in tissue
composition. A simultaneous PET/MR system
has recently been installed and will commence
operation soon. It will be used to improve tu-
mour characterisation, individualised therapy
planning and therapy monitoring, while con-
currently reducing radiation burden for the
patient.
ESSENTIAL PUBLICATIONS: (1.) Re T.J. et al. (2011). En-
hancing pancreatic adenocarcinoma delineation in
diffusion derived intravoxel incoherent motion f-
maps through automatic vessel and duct segmenta-
tion. Magn. Reson. Med., 66, 13271332. (2.) Bauman
G. et al. (2011) Pulmonary Functional Imaging: Qual-
itative Comparison of Fourier Decomposition MR
Imaging with SPECT/CT in Porcine Lung. Radiology,
260, 551519. (3.) Hillengass J. et al. (2011) Diffusion-
weighted imaging for non-invasive and quantitative
monitoring of bone marrow inltration in patients
with monoclonal plasma cell disease: a comparative
study with histology. Br. J. Haematol, 153, 721728. (4.)
Hadaschik B.A. et al. (2011). A novel Stereotactic Pros-
tate Biopsy System Integrating Preinterventional
MRI and Live US fusion. J. Urology, in press.
are conducted in cooperation with partners
from medical-technical and pharmaceutic in-
dustries. Clinical studies are performed in close
cooperation with clinics and institutes of the
Heidelberg University hospital and the Nation-
al Center for Tumor Diseases (NCT) Heidelberg.
The Devision is furthermore a partner of the
German Consortium for Translational Oncol-
ogy and the German Center for Lung Research.
Scientic elds of application include e.g. early
detection and characterization of prostate can-
cer, lung cancer and multiple myeloma. A novel
biopsy system combining preinterventional
MRI with peri-interventional ultrasound for
perineal prostate biopsies is applied in co-oper-
ation with the Department of Urology at Hei-
delberg University Hospital, enabling precise
diagnosis of prostate cancer. In addition, tools
for quantifying individual therapy response
are developed and applied in patients with e.g.
rectal carcinoma or malignant melanoma. Fur-
ther activities include the computer-aided im-
age handling for implementation of the com-
plex image information in patient care, e.g. for
improving radiotherapy.
Future Outlook:
Our Goal is the progress of individualized diag-
nostics and therapy and image-guided therapy.
A clinical study with MR-guided intra-urethral
thermotherapy using high-intensity focused
ultrasound (HIFU) is planned. Ultra-high eld
MRI is currently applied for advanced imaging
of brain tumors. Novel contrast media (CEST
agents) will be developed. Diffusion-weighted
MRI for staging and therapy control is applied
in patients with multiple myeloma. A cohort
study supported by the Jose-Carreras-founda-
tion for evaluating prognostic signicance of
perfusion data from dynamic MRI is currently
in progress. In patients with bronchogenic car-
cinoma, novel approaches are developed for
metabolic MRI, 4D-CT imaging and PET with
new radiotracers. The CT-based lung cancer
screening and intervention trial (LUSI study)
for early detection of bronchogenic carcinoma
Patient with a cerebral glioblastoma of
the left hemisphere. Axial high-resolution
T2-weighted MR at 7.0 Tesla demonstrating
tumor localization and heterogeneity.
Medical Physics in Radiology
Division
Head: Prof. Dr. Dr. Wolfhard Semmler
Medical Physics in Radiology (E020)
69120 Heidelberg
Tel: +49 6221 42 2550
Fax.: +49 6221 42 2585
E-Mail: semmler.office@dkfz.de
The Devision of Medical Physics in Radiol-
ogy plays a pivotal role in all imaging-based
procedures, developing new and optimizing
existing imaging methods. In order to optimize
and individualize a cancer patients treatment
and local tumor control, quantitative biomedi-
cal information about metabolic, physiologic
and functional parameters of tumors is es-
sential. We are establishing new methods and
technologies of cancer diagnostics and are
improving existing ones, e.g. expanding the
diagnostic value of 7T MRT by Na-23 and O-17
imaging, extending noninvasive diagnostic
methods. Through the development of MRT
diffusion measurement techniques, we gain
additional information about cellular mem-
branes and incoherent capillary ow in tumor
tissue. Furthermore, we develop noninvasive
diagnostic methods for the assessment of
blood ow, mean transit times and perfu-
sion in body organs and in particular tumors,
as well as imaging techniques for detection
and in vivo characterization of experimental
metastases on the micro-morphological, func-
tional and molecular level. We develop new de-
signs and devices (e.g. nanosurfaces), chemical
syntheses, and the re-formulation of current
active compounds for study and intervention
of biological processes, including those related
to genetic diseases. These products permit all
conceivable biophysical techniques (high eld
MRT, CT, PET, NIR imaging) to monitor the mo-
lecular processes in a relevant pharmacological
context.
Future Outlook:
The major objectives for the future will be re-
search projects with the 7T-system; molecular
imaging with a focus on metastatic processes;
futher development of interventional pro-
cedures, and of photon-based small-animal
emission tomographic systems. To fulll these
objectives, the Departments ve-year plan is
to:
qualify the Department as a center of ex-
cellence in oncologic imaging methodol-
ogy and continue and strengthen the sup-
port for the clinical departments.
develop and introduce new MR imag-
ing methods suitable for oncological
diagnostics and therapy, in particular for
7T eld strength, but also for the 3T and
1.5T-systems.
implement a new working group con-
cerned with high-end CT development
and reconstruction algorithm.
develop new experimental multimodal
imaging modalities and pave the way for
molecular and functional imaging, in par-
ticular imaging of metastases.
participate in the development of a com-
bined MRI-Linac-system to enhance online
position control and online motion correc-
tion to further improve radiotherapy.
ESSENTIAL PUBLICATIONS: (1.) Laun, F.B. (2011). Deter-
mination of the dening boundary in nuclear mag-
netic resonance diffusion experiments. Physical Re-
view Letters. (2.) Nagel, A.M. (2009). Sodium MRI
using a density-adapted 3D radial acquisition tech-
nique. Magnetic Resonance in Medicine, 62, 1565
1573. (3.) Buerle, T. (2008). Bevacizumab inhibits
breast cancer induced osteolysis, surrounding soft
tissue metastasis and angiogenesis in rats as vis-
ualized by VCT and MRI. Neoplasia, 10, 511520. (4.)
Kiessling, F. (2004). Volumetric computed tomogra-
phy (VCT): a new technology for noninvasive, high-
resolution monitoring of tumor angiogenesis. Nature
Medicine, 10, 11331138.
3D reconstruction of the
oxygen-17 MR data set of the
human brain. Due to the low
natural abundance of the
oxygen isotope
17
O images of
the brain can only be acquired
in reasonable measurement
times at high eld strengths.
Research Program 98
Head: Prof. Dr. Michael Eisenhut
Radiopharmaceutical Chemistry
Division
Radiopharmaceutical Chemistry (E030)
69120 Heidelberg
Tel: +49 6221 42 2443
E-Mail: m.eisenhut@dkfz.de
Research at the Devisionof Radiopharmaceuti-
cal Chemistry is focussed on the development
of new pharmaceuticals, which have potential
for molecular imaging and tumor therapy. Tu-
mor-specic carrier molecules are labeled with
radioisotopes, leading to targeted accumula-
tion in cancer cells. These Radiopharmaceu-
ticals serve as molecular probes for positron
emission tomography (PET) and single photon
emission computerized tomography (SPECT).
Radiopharmaceuticals provide information
on functional and structural properties of
organs and tumors, on pathological changes
in tissues, on perfusion dynamics in diseased
organs, on local distribution, availability, and
effect of drugs, and on the time course of vari-
ous therapy procedures, their consequences
and benets. Radiopharmaceuticals provide
information about the localization of tumors
as well as the function of various organs. In
addition, information about distribution, avail-
ability and efcacy of drugs can be monitored
to visualize the effectiveness of therapy. In
nuclear medicine several radiopharmaceuti-
cals are successfully applied for internal radio-
therapy. In addition to our own research, the
devision provides radiopharmaceuticals for the
support of patient care at the Clinical Coopera-
tion Unit Nuclear Medicine (E060). Necessary
requirements for clinical applications are the
maintenance of GMP-conform production and
documentation for the pharmaceutical inspec-
tion control.
Future Outlook:
Development of novel radiopharmaceuticals:
Urea derived PSMA inhibitors for the imaging
and therapy of prostate cancer. Radiopharma-
ceuticals for the therapy-related imaging of
apoptosis and necrosis.Radiopharmacy: Exten-
sion of GMP facility.
ESSENTIAL PUBLICATIONS: (1.) Kubas H. et al. (2010).
Multivalent Cyclic RGD-Ligands: Inuence of Link-
er Lengths on Receptor Binding. Nuclear Medicine
and Biology, 37, 885891. (2.) Eder M. et al. (2010).
ScVEGF-PEG-HBED-CC and scVEGF-PEG-NOTA conju-
gates: comparison of easy-to-label recombinant pro-
teins for [68Ga]PET imaging of VEGF receptors in an-
giogenic vasculature. Nucl Med Biol, 37, 405412. (3.)
Eder M. et al. (2010). 68Ga-labelled recombinant an-
tibody variants for immuno-PET imaging of solid tu-
mours. Eur J Nucl Med Mol Imaging, 37, 13971407.
(4.) Oltmanns D. et al. (2009). Benzamides as mel-
anotropic carriers for radioisotopes, metals, cytotox-
ic agents and as enzyme inhibitors. Curr Med Chem.,
16, 20862094.
Two radiopharmaceuticals,
[18F]FDG and [18F]
FLT, showing as an
example for molecular
imaging a patient
with an oropharynx
CA. The differences of
physiological uptake
in brain (FDG) and
bone marrow (FLT) are
noteworthy.
Medical Physics in Radiation Oncology
Division
Head: Prof. Dr. Wolfgang Schlegel
Medical Physics in Radiation Oncology (E040)
69120 Heidelberg
Tel: +49 6221 42 2551
E-Mail: w.schlegel@dkfz.de
Because failure of local tumor control is still
a problem in many cancer patients, there is
an urgent need to optimize existing and to
develop new and more effective radiotherapy
techniques for localized tumors. Research at
our devision is focusing on new conformal ra-
diotherapy techniques with photons, electrons,
protons and heavy ions. In the framework of
ongoing projects in photon and ion therapy,
the division future work will concentrate on
the consideration of dynamic changes of tar-
get volumes and organs at risk under therapy,
due to therapeutic response, organ movement
or patient repositioning. Image-guided and
time-adapted therapy is being developed to
combine conformal dose delivery with online
imaging of 3D anatomy and online monitoring
of 3D dose distributions. The devision is fur-
thermore integrating molecular imaging into
treatment planning and dose delivery with the
goals of boosting radio-resistant tumor sub-
volumes and avoiding radiosensitive normal
tissue structures. Establishing mathematical
and biological models of tumor and normal
tissue response is a further tool to optimize
treatment schemes and techniques. One of the
strengths of the devision is the direct transfer
of prototypes of software and hardware de-
velopment into clinical applications in close
collaboration with the Clinical Cooperation
Unit Radiation Oncology. Thus the devision
is also active in testing and evaluating new
techniques, as well as in establishing adequate
quality assurance programs.
Future Outlook:
The future research and development projects
comprise the elds of image-guided radiothe-
rapy (IGRT), biological adaptive radiotherapy,
ion therapy and the physical parts of different
radiation biology projects. Research related to
IGRT with photons will be followed by a phase
where the results are transferred to the clinical
application at DKFZ. We want to accompany
the development of real-time 3D-imaging of
the patient in treatment position. Promising
new approaches involve combinations of MR-
imaging or 3D x-ray imaging with a new gen-
eration of treatment machines. To support the
general aim of a biologically guided radiother-
apy at DKFZ, we will pursue the development
of a unied treatment planning and optimiza-
tion platform that specically accounts for the
information provided by biological input data.
In heavy ion therapy, new dosimetric methods
will be developed. A project for Monte Carlo
simulation of the effects of secondary elec-
trons in the dosimetry of heavy ions and the
investigation of perturbation factors for ioniza-
tion chamber dosimetry has been started. The
possibility to use radiographic imaging with
ion beams will be investigated for ion beam
treatment. In the eld of radiobiological mod-
eling, the existing model shall be extended by
incorporating a patient model and information
obtained in biological imaging. With these de-
velopments, it will also be possible to apply the
model in clinical tumors.
ESSENTIAL PUBLICATIONS: (1.) Echner G.G. et al.
(2009). The design, physical properties and clinical
utility of an iris collimator for robotic radiosurgery.
Phys Med Biol, 54, 53595380. (2.) Kyas I. et al. (2007).
Prediction of radiation-induced changes in the lung
after stereotactic body radiation therapy of non-
small-cell lung cancer. Int J Radiat Oncol Biol Phys, 67,
768774. (3.) Harting C. et al. (2010). Computer sim-
ulation of tumour control probabilities after irradia-
tion for varying intrinsic radio-sensitivity using a sin-
gle cell based model. Acta Oncologica, 49, 13541362.
(4.) Schlegel W. et al. (2010). If you cant see it, you
can miss it: the role of biomedical imaging in radia-
tion oncology. Radiation Protection Dosimetry, 139,
321-326.
The IRIS-collimator was developed in
collaboration with Accuray Inc. for
the dynamic beam collimation of the
Cyberknife accelerator system. It has been
shown,that with the use of this collimator
the beam delivery times can be reduced
by a factor of 2 to 3, while maintaining
or even improving the quality of the dose
distributions (Echner et al., 2009).
Research Program 100
Head: Prof. Dr. Dr. Jrgen Debus
Radiation Oncology
Clinical Cooperation Unit
Radiation Oncology (E050)
69120 Heidelberg
Tel: +49 6221 42 2515
E-Mail: j.debus@dkfz.de
The Clinical Cooperation Unit Radiation Oncol-
ogy treats cancer patients with new innova-
tive technologies in challenging situations.
It explores new approaches and pushes the
boundaries of modern radiation oncology.
This involves the combination of different
radiotherapy techniques such as intensity
modulated radiotherapy (IMRT), intraoperative
radiotherapy and brachytherapy. New software
solutions for optimzed combination of photon
and particle treatment in cooperation with the
Heidelberg Ion Therapy facility (HIT) are being
established. One research focus is the treat-
ment of moving tumors in the lung and upper
abdomen. Breathing motion adjusted therapy
is applied in so called gated therapy; Radia-
tion is only delivered in the optimal breath-
ing phase and thus safety margins can be
minimized and dose exposure to surrounding
tissues lowered. Different markers invasively
placed around the tumor are evaluated to im-
prove imaging of tumor motion and allow for
gated or tracked therapy. This includes gold
markers for x-ray based uroscopy imaging
and electromagnetic markers for online tumor
motion tracking. Another option in high preci-
sion radiotherapy is rotational intensity-mod-
ulated therapy (IMRT). Its possibilities alone or
in combination with static gantry IMRT (hybrid
arc) are being explored. Another research focus
is the evaluation of functional imaging in the
planning of radiotherapy. This includes meta-
bolic and hypoxic tracers and their potential to
individualize radiation treatment of non-small
cell lung cancer.
Future Outlook:
In cooperation with the department of diag-
nostic radiology, the use of an MRI/PET for
target denition and treatment planning in ra-
diation oncology will be explored. This includes
new radiotracers and special MRI sequences
for whole body imaging and the detection of
lymph node metastases. In addition, the in-
tegration of MR imaging into image guided
radiotherapy (IGRT) shall be established. In an
initial step two separate machines a linear
accelerator and an independant 1.5 T MR are
planned to be linked with a patient shuttle to
allow MRI based position control and correc-
tion. The aim is to minimize additional dosage
(especially in younger patients and children)
and to improve soft tissue contrast for tumor
position detection. The next step in
this evolution of modern IGRT is go-
ing to be a linear accelerator-MRI
combination in one machine for ac-
celerated workow and online tumor
imaging. A clinical focus will be on
the possibilities of radiosurgery of
spinal tumors. While this is tradition-
ally the domain of conventional radi-
otherapy, new options for radiosurgi-
cal approaches will be tested in a prospective,
randomized manner.. New radiotherapy op-
tions using a robotic arm approach for indivi-
ualized and personalized targeted radiation
oncology are also on the agenda. The expan-
sion of radiosurgical and fractionated therapy
options is the goal. In medical oncology a re-
markable ood of new substances targeting
specic tumor pathways has been seen. The
combination of these drugs with radiation
therapy and the implications for normal tis-
sue toxicity is a major challenge in the future
and shall be addressed in an experimental and
clinical setting to ensure the safety of these
multimodal cancer therapy approaches.
ESSENTIAL PUBLICATIONS: (1.) Roeder F et al. (2012).
Aggressive local treatment containing intraoperative
radiation therapy (IORT) for patients with isolated lo-
cal recurrences of pancreatic cancer:a retrospective
analysis. BMC Cancer, 12, 295. (2.) Roeder F. et al. (2011).
Intensity modulated or fractionated stereotactic reir-
radiation in patients with recurrent nasopharyngeal
cancer. Radiat Oncol, 6, 22. (3.) Zwicker F. et al. (2011).
Reirradiation with intensity-modulated radiothera-
py in recurrent head and neck cancer. Head Neck, 33,
16951702. (4.) Sterzing F. et al. (2009). Intensity mod-
ulated radiotherapy (IMRT) in the treatment of chil-
dren and adolescents--a single institutions experi-
ence and a review of the iterature. Radiat Oncol, 4, 37.
Intensity-modulated radiotherapy of a
pelvic tumor. Individualized beams from 9
directions enable personalized treatment
with sparing of sensitive structures such as
small bowel, bladder and genitals (Raystation
planning software, Raysearch Laboratories,
Stockholm, Sweden).
Molecular Radiooncology
Head: Prof Dr. Dr. Peter Huber
Molecular Radiooncology (E055)
69120 Heidelberg
Tel: +49 06221 42 2515
E-Mail: p.huber@dkfz.de
The goal of current molecular research in
Radiation Oncology is to work towards a per-
sonalized medicine program, applying high-
throughput methodologies in preclinical and
translational research trials. Genetic key players
in radioresistance and the determinants of re-
currences after radiotherapy are being investi-
gated to broaden the therapeutic window and
improve clinical outcome in radiotherapy can-
cer patients. To this end, we are conducting in-
vestigations in preclinical and clinical research
in the following areas
Can radiation favorably be combined with
specic signaling inhibitors to enhance
therapeutic anti-tumor efcacy +/- CTX of
VEGF, PDGF, EGF, Integrins, TGF-beta etc.?
Can combinations of signaling inhibitors
(PDGF, TGF-beta, CTGF) attenuate radio-
therapy-associated side effects such as
lung brosis?
Prospective trials investigating the im-
mune stimulatory effects of low dose ir-
radiation in tumor patients (pancreatic
cancer, liver metastases from CRC).
Translational clinical studies investigating
if radiotherapy (IMRT) can be successfully
combined with EGFR or other signaling in-
hibitors in NSCLC and pancreatic cancer
The molecular basis of the efcacy of car-
bon ion/particle radiotherapy
The network governing the angiogenic
switch or other balanced systems in irradi-
ated cancer
The feasibility of MRI-guided focused ul-
trasound induced tumor therapy
New clinical concepts of intensity-modu-
lated radiotherapy treatment using bio-
physical/molecular/functional imaging
strategies.
Future Outlook:
An important goal for Radiation Oncology in
the future is the systematic analysis of molecu-
lar radiation effects. Aims are the integration of
radiation research topics with high through-
put biology and radiology platform technolo-
gies, such as genomics, functional genomics,
epigenetics, proteomics, siRNA screening, bio-
informatics, systems biology approaches and
molecular and macroscopic radiological imag-
ing. These categories will be linked to classi-
cal cancer research expertise in areas such as
apoptosis, immunology, stem cell biology, an-
giogenesis, brogenesis, and carcinogenesis or
signal transduction. A major goal of Molecular
Radiation Oncology is the clinical and biomedi-
cal analysis of radiation tumor/normal tissue
biology. Key genetic players of radiation effects
can be identied by global expression proling
(genomics/proteomics)
and sequencing studies in tumor/blood sam-
ples in preclinical cell and animal studies, but
also in cancer patients undergoing clinical
trials. The promising targets can be further
functionally evaluated for their ability to
modulate radiotherapy response by knock outs
or pharmacological intervention. The resulting
data can then be used to rationally design tar-
geted drug cocktails for preclinical cell and
animal research and nally, for the translation
to cancer patients. To optimize and personalize
cancer therapies in the future, we will perform
bench-to-bedside research including initiation
and conduction of clinical studies.
ESSENTIAL PUBLICATIONS: (1.) Flechsig P. et al. (2012).
LY2109761 attenuates radiation-induced pulmonary
murine brosis via reversal of TGF-beta and BMP as-
sociated proinammatory and proangiogenic sig-
nals. Clin Cancer Res 18, 36163627. (2.) Zhang M.
(2011). Blockade of TGF-beta signaling by the TGFR-I
kinase Inhibitor LY2109761 enhances radiation re-
sponse and prolongs survival in glioblastoma. Can-
cer Research, 71, 71557167. (3.) Timke C. (2011) Ran-
domized controlled phase I/II study to investigate
immune stimulatory effects by low dose radiothera-
py in primarily operable pancreatic cancer. BMC Can-
cer, 11, 134. (4.) Abdollahi A. (2007). Transcriptional
network governing the angiogenic switch in human
pancreatic carcinoma. PNAS, 104, 1289012895.
Magnetic resonance imaging of a mouse brain
with a glioblastoma tumor. Blockade of TGF-
beta signaling by the TGFR-I kinase Inhibitor
LY2109761 (LY) enhances radiation response
(RT) and prolongs survival in glioblastoma in
an orthotopic mouse model.
Head: Prof. Dr. Uwe Haberkorn
Nuclear Medicine
Nuclear Medicine (E060)
69120 Heidelberg
Tel: +49 6221 42 2477
E-Mail: u.haberkorn@dkfz.de
The Clinical Cooperation Unit Nuclear Medi-
cine is involved in multiple projects on topics
such as the planning and follow up of chemo-
or radiation therapy, pharmacokinetic model-
ling of dynamic PET data, identication of new
peptides with high afnity for tumor disease;
the establishment of new endoradiotherapy
approaches based on peptides and antibodies;
the development of alternate panning strate-
gies with phage and ribosome display using
recombinant proteins, membrane fractions
and cells; the design of combination therapy
with endoradiotherapy and chemo-, immuno-
or radiation therapy; and the establishment of
new treatments for non-iodine-concentrating
thyroid carcinoma.
Future Outlook:
One major topic for the CCU Nuclear Medi-
cines future research will be the identica-
tion of possible targets for new radiophar-
maceuticals. For this purpose the gene array
data obtained from correlative PET and tumor
specimen evaluations are screened for recep-
tors and cell surface proteins. Following the
identication of possible targets, the partners
at the MPI Saarbrcken are using their FLEXx
software, a small molecule docking software,
to identify substances with a high likelihood of
binding to the identied structures.
The identication of new ligands will be one
of the main areas of research in the labora-
tory. The group intends to apply biotechnology
methods such as display (phage and ribosome
display) of libraries consisting of scaffold pro-
teins. This project addresses the identication
of specic binders to targets overexpressed
in a variety of tumors by using peptide librar-
ies. We will concentrate on target structures
identied either by literature research or by
gene proling data available at the campus.
In the last 18 months we started intra-arterial
therapy with DOTATOC in patients with me-
tastasized neuroendocrine tumors using
90
Y,
177
Lu and
213
Bi. This program will be extended
to other peptides/receptors. Furthermore,
novel treatment strategies using radiolabelled
benzamides in melanoma patients and PSMA
ligands in patients with prostate carcinoma
have been initiated and will be pursued fur-
ther.
ESSENTIAL PUBLICATIONS: (1.) Kratochwil C. et al.
(2010). Intraindividual comparison of selective ar-
terial versus venous 68Ga-DOTATOC-PET/CT in pa-
tients with gastroenteropancreatic neuroendocrine
tumors. Clin Cancer Res, 16, 28992905. (2.) Strauss
L.G. et al. (2011). Shortened acquisition protocols for
the quantitative assessment of the 2-tissue compart-
ment mod-el using dynamic PET/CT 18F-FDG stud-
ies. J Nucl Med, 52, 379385. (3.) Askoxylakis V. et al.
(2010). A New Peptide Ligand for Targeting Human
Car-bonic Anhydrase IX, Identied through the Phage
Display Technology. PLoS One 5:e15962. (4.) Altmann
A. et al. (2010). Therapy of thyroid carcinoma with the
histone deacetylase inhibitor MS-275. Eur J Nucl Med
Mol Imaging, 37, 2286-2297.
DOTATOC-PET in a patient with
metastasized neuroendocrine
tumor.
Medical and Biological Informatics
Division
Head: Prof. Dr. Hans-Peter Meinzer
Medical and Biological Informatics (E130)
69120 Heidelberg
Tel: +49 6221 42 2354
E-Mail: h.p.meinzer@dkfz.de
Research in our division aims at improving
diagnostic methods and treatment planning
based on imaging technologies, such as com-
puter tomography, magnetic resonance to-
mography and ultrasound.
The division is currently active in different
research areas of medical imaging, includ-
ing image analysis for tissue differentiation,
simulation and diffusion imaging. A recently
established junior group is working on new
methods in the eld of computer assisted in-
terventions.
Central to our work is the idea of translational
research, i.e. translating our ndings, meth-
ods and software to the patient in the clinic.
Therefore, we are closely collaborating with
a large number of national and international
hospitals, as well as various engineering insti-
tutes. Furthermore, we established a quality
management process for our central software
platform MITK (Medical Imaging Interaction
Toolkit).
Future Outlook:
Since 2002 MITK, which is the central element
of our research, has been the basis for all de-
velopments of the devision of Medical and
Biological Informatics and is undergoing con-
tinuous development. In a joint effort to facili-
tate the international collaboration between
different research groups, the Common Toolkit
(CTK) project was initiated in 2009 by Prof.
Dr. Ron Kikinis (Harvard Medical School) and
Prof. Dr. Hans-Peter Meinzer, head of the MBI
division. In this initiative, different research
groups and companies from around the world
are together developing a new common basis
for software development in medical imaging.
Another central orientation is microstructur-
al analysis of the brain based on diffusion-
weighted magnetic resonance imaging (dMRI).
As an example dMRI can help in detecting
Alzheimer disease at an early stage. In surgi-
cal navigation, we are focusing on markerless
localization of patient and instruments by
means of Time-of-Flight (ToF) cameras which
provide depth information in addition to a
standard two-dimensional image. Concerning
image analysis, we are involved in an obesity
study with over 1200 patients. Further work
focuses on automated differentiation of fat
tissue in whole body MR images, which allows
for examining the inuence of distinct fat tis-
sue types. A very recent development in our
division is the use of portable devices, such as
tablet computers, as both a radiological viewer
and to assist surgical navigation. Additionally,
the division is part of the recently established
collaborative research center Cognition Guid-
ed Surgery.
ESSENTIAL PUBLICATIONS: (1.) Fritzsche K.H. et al.
(2012). MITK Diffusion Imaging. Methods of Informa-
tion in Medicine, Methods Inf Med., 51, 441418. (2.)
van Bruggen T. et al. (2012). Do Alzheimer specic mi-
crostructural changes in mild cognitive impairment
predict conversion? Psychiatry Res, 203(2-3), 184193.
(3.) Wald D. et al. (2012). Automatic Quantication
of Subcutaneous and Visceral Adipose Tissue from
Whole-Body Magnetic Resonance Images suitable
for Large Cohort Studies. Journal of Magnetic Reso-
nance Imaging, 36, 14211434. (4.) Maier-Hein L. et al.
(2012). Convergent Iterative Closest-Point Algorithm
to Accomodate Anisotropic and Inhomogenous Lo-
calization Error. IEEE Transactions on Pattern Analysis
and Machine Intelligence, 34, 15201532.
Three-dimensional
reconstruction of an
individual liver. The blood
supply through the portal
vein (light blue), the hepatic
veins (dark blue), arteries
(red), gall bladder (green)
and three tumors (red),
including safety margins
(yellow), are shown.
Head: Prof. Dr. Stefan Hell
Optical Nanoscopy
Division
Optical Nanoscopy (E190)
69120 Heidelberg
Tel: +49 6221 54 51210
and +49 551 201 2500
E-Mail: s.hell@dkfz.de
and Max Planck Institute for Biophysical
Chemistry in Gttingen, Department of
NanoBiophotonics
The resolution of light microscopes has been
generally limited by the wavelength of light to
about 250 nanometers. We have developed the
rst uorescence microscopes capable of pro-
viding images with a resolution of fractions of
lights wavelength from the interior of a cell. A
combination of two of our approaches, namely
4Pi and STED microscopy, makes it possible to
achieve resolutions under 40 nanometers in
all directions. This enables us to observe bio-
logical structures that are 2000 times thinner
than a human hair. We are now trying to nd
out how we can achieve and exploit resolu-
tions in the range of a few nanometers to
fundamentally advance biological and clinical
research.
Future Outlook: Our goal is to develop tech-
niques such as STED (Stimulated Emission
Depletion Microscopy) to unveil sub-cellular
structures at a resolution level of a few 10 nm
in a living cell. After all, every disease manifests
itself rst in the cells. We are now exploring
how the breakthrough in light microscopy res-
olution can be translated into fundamental ad-
vancements in biological and clinical research.
STED light microscopy makes it possible to
study the causes of diseases more closely and
thus to speed up development of medications.
ESSENTIAL PUBLICATIONS: (1.) Chojnacki J. et al. (2012).
Maturation-Dependent HIV-1 Surface Protein Redis-
tribution Revealed by Fluorescence Nanoscopy. Sci-
ence, (in press). (2.) Vicidomini G. et al. (2012). STED
with wavelengths closer to the emission maximum.,
Opt Express, 20, 52255236. (3.) Bingen P. et al. (2011).
Parallelized STED uorescence nanoscopy. Opt Ex-
press, 19, 2371623726. (4.) Berning S. et al. (2012). Na-
noscopy in a living mouse brain. Science, 335, 551.
Vimentin network of mammalian
cell revealed by STED uorescence
microscopy with subdiffraction
spatial resolution.
Translational Radiation Oncology
Max-Eder-Junior Research Group
Abdollahis group was one of the rst to em-
ploy genome-wide transcriptional analysis and
protein phosphorylation analysis to systemati-
cally investigate the perturbation of the cellu-
lar homeostasis induced by ionizing radiation
and anti-/pro-angiogenesis. These discoveries
have built a foundation to better understand
inter-cellular communication and intra-cellu-
lar signalling principles induced by radiation
and angiogenesis modulators, and unravelled
key mechanisms governing tumor therapy re-
sistance a major obstacle of cancer therapy.
Their data indicate that tumor-stroma and
tumor-vessel communication i.e., microvas-
culature endothelial cells, constitute a critical
target of conventional cancer therapies, such
as radiation and chemotherapy. Subsequently,
molecular, cellular and physiological rationales
for the benecial use of trimodal cancer thera-
py (consisting of anti-angiogenesis, radiother-
apy and chemotherapy) were provided. The
translational impact of this research on the
development of novel clinical protocols is evi-
dent from the growing number of trimodal tri-
als in solid tumors initiated in Heidelberg and
worldwide. Intriguingly, they could also show
that inhibition of PDGF signaling ameliorates
the development of radiation-induced lung
brosis, a critical side effect and dose limiting
normal tissue response of radiotherapy. In ad-
dition, this group has recently discovered the
potential of peripheral blood transcriptome
and miRs as a sentinel organ to properly detect
tumor stage and predict clinical outcome.
Future Outlook:
A major goal of this group is to generate an
integrative molecular biology platform for
identication of cell-cell and intracellular sign-
aling networks induced by photon, proton and
carbon irradiation incorporating transcrip-
tomics, miRNA, epigenomics, proteomics and
functional genomics approaches. These data
will be instrumental in identication of novel
molecular targets for modulating the radiation
response, i.e., enhancing the anti-tumor effects
while sparing surrounding normal tissue from
radiation induced damage. They further aim
to better understand the mechanism of local
invasion and distant metastasis of tumors.
The eld of radiotherapy still lacks powerful
biomarker and molecular classiers of therapy
response. Accordingly, they seek to design pe-
ripheral blood transcriptome and miRNA based
patient classier that would assist clinicians in
selecting those patients likely to benet most
from the local multimodal therapies. Finally,
thegroup aims to optimize local tumor control
via rational design of multimodal therapies
consisting of radiotherapy and tumor stroma
targeting agents. A critical step towards this
goal is the systematic investigation of com-
pensatory mechanisms that render tumors
resistant to radiotherapy and targeted i.e., an-
tiangiogenic, cancer therapies.
ESSENTIAL PUBLICATIONS: (1.) Abdollahi A. et al.
(2010). Evading tumor evasion: Current concepts and
perspectives of anti-angiogenic cancer therapy. Drug
Resist Updat. 13, 1628. (2.) Almog N. et al. (2009).
Transcriptional Switch of Dormant Tumors to Fast-
Growing Angiogenic Phenotype. Cancer Research.,
69, 836844. (3.) Abdollahi A. et al. (2007). Transcrip-
tional network governing the angiogenic switch in
human pancreatic cancer. Proc Natl Acad Sci U S A.
104, 128901285. (4.) Abdollahi A. et al. (2005). Inhibi-
tion of platelet-derived growth factor signaling at-
tenuates pulmonary brosis. J Exp Med. 201, 925935.
Head: Dr. Dr. Amir Abdollahi
Translational Radiation Oncology (E210)
69120 Heidelberg
Tel: +49 6221 56 39604
E-Mail: a.amir@dkfz.de
From left: establishment of rst preclinical models
of lung irradiation with carbon ions, examples for
verication of carbon ion dose distribution by PET/
CT, evaluation of radiation-induced lung toxicity
and microvascular damage. Clinical translation
(right): irradiation of the rst lung cancer patient
with carbon ions at HIT in fall 2011.
Head: Dr. Lena Maier-Hein
Computer-assisted Interventions (E131)
69120 Heidelberg
Tel: +49 06221 42 2341
E-Mail: l.maier-hein@dkfz.de
Medical interventions involving minimally-
invasive access to the internal anatomy of the
patient are continuously gaining importance
in the diagnosis and treatment of cancer and
other diseases. The safety, efciency and suc-
cess of such interventions crucially depend on
the precise navigation of medical instruments
through the patients body, while taking criti-
cal structures into account. However, mental
fusion of the partially visible anatomy with
high-resolution pre-operative tomographic im-
ages and/or surgical planning data in the pres-
ence of organ motion is extremely challenging.
Our multidisciplinary research group, which is
associated with the Division of Medical and Bi-
ological Informatics, combines expertise from
computing, physics and medicine in order to
develop new concepts for computer-assisted
medical interventions. Our focus is on techno-
logical innovation with a strong emphasis on
clinical translation and direct patient benets.
Current research topics include robust and fast
3D localization of the patient anatomy using
range imaging techniques, such as Time-of-
Flight, real-time fusion of multi-modal patient
data based on surface registration and new
tracking techniques, as well as innovative hu-
man-computer interfaces. Further core areas
include the modeling and propagation of sys-
tem errors as well as workow optimized ap-
proaches to computer guidance that balance
the patient benets with the complexity and
cost of the assistance system.
Future Outlook:
In the eld of computer-assisted medical inter-
ventions, the immense capabilities of comput-
ers in terms of storing and processing huge
amounts of data have not yet been fully exploit-
ed. The vision of our group is to improve patient
care by an objective, context-aware and com-
bined analysis of all relevant data in the course
of disease treatment. Dynamically acquired fac-
tual and practical knowledge (e.g. study results,
clinical outcomes in similar cases) as well as in-
dividual patient data (e.g. laboratory data, pre-
operative images, intra-operative sensor data)
shall be continuously accumulated and pro-
cessed to support the physicians decisions and
actions in a knowledge-based manner. Com-
puter assistance shall cover the entire medical
workow from treatment planning, to plan
execution, to follow-up, thereby supporting
the physician without adding complexity or
time compared to the conventional procedure.
To maximize patient safety, the uncertainties
associated with the different sources of in-
formation applied in the course of computer-
assisted treatment shall be properly modeled,
propagated and fused. Finally, a exible techni-
cal infrastructure will allow straightforward
integration of new algorithms and devices and
fast adaption to the dynamic advances in sur-
gical and interventional techniques. Eventually,
holistic analysis of all relevant data, objectivity
in data interpretation and context-aware as-
sistance will lead to improved clinical outcome.
ESSENTIAL PUBLICATIONS: (1.) Maier-Hein L. et al.
(2012). Convergent iterative closest-point algorithm
to accomodate anisotropic and inhomogenous lo-
calization error. IEEE T Pattern Anal, 34, 15201532.
(2.) Seitel A. et al. (2011). Computer-assisted trajecto-
ry planning for percutaneous needle insertions. Med
Phys, 38, 32463259. (3.) dos Santos T.R. et al. (2010).
Correspondences search for surface-based intra-op-
erative registration. In Med Image Comput Com-
put Assist Interv, 13(Pt2), 660667. (4.) Maier-Hein,
L. (2008). In vivo accuracy assessment of a needle-
based navigation system for CT-guided radiofrequen-
cy ablation of the liver. Med Phys, 35, 53855396.
Computer-assisted radiofrequency ablation (RFA)
of the liver
Computer-assisted Interventions
Viruses play a crucial role in a number of cancers. This Research Pro-
gram investigates the mechanisms by which viruses cause cancer
and the ways by which the body defends itself. In addition, resear-
chers are isolating and characterizing unknown viruses from tumor
material. Special attention is directed to the diagnosis, prevention,
and treatment of such viral infections. Furthermore, scientists are
working on methods using viruses to selectively kill cancer cells
or as vehicles for introducing therapeutic genes into cells. Current
focuses of tumor-virological research are:
Papilloma viruses and their role in cancers of the genital or-
gans, the mouth and throat, and the skin
Parvoviruses as direct inhibitors of tumor growth and as gene
vectors for cancer treatment
Retroviruses (HIV, spumaviruses) for developing specic thera-
pies
Anelloviruses (TT viruses) and their effect on the host cell
genome
Herpesviruses (Epstein-Barr viruses) in the development of
malignant tumors and as gene vectors for cancer therapy.
Coordinator
Prof. Dr. Lutz Gissmann
108 Research Program
Head: Prof. Dr. Jean Rommelaere
Tumorvirology
Division
Tumorvirology (F010)
69120 Heidelberg
Tel: +49 6221 42 4960
E-Mail: j.rommelaere@dkfz.de
The Division Tumor Virology should actually be
called Anti-Tumor Virology since its objective
is to develop oncolytic viruses (preferentially
killing tumor cells) and viral vectors (transfer-
ring therapeutic genes into diseased, including
cancer, cells). Our activities have led to the
launching of a clinical trial using the oncolytic
parvovirus H-1PV to treat malignant gliomas,
and the advanced validation of adeno-asso-
ciated virus (AAV)-based vectors. Three main
research axes are presently developed.
1. Investigation of the interactions of onco-
lytic parvoviruses (PV) with host cells, in
particular
(i) cellular markers predictive of tumor re-
sponsiveness to PV treatment,
(ii) PV determinants of host range,
(iii) molecular pathways involved in PV
oncotoxic and immuno-modulating prop-
erties,
(iv) PV-mediated delivery of cyto- and
chemokines into tumors and their micro-
environment.
2. Proofs of concept for future clinical trials
using oncolytic parvoviruses, including
(i) preclinical evaluation of the applicabil-
ity of H-1PV therapy to malignancies in
children and adolescents,
(ii) development of novel anticancer strat-
egies based on combining of H-1PV with
epigenetic modulators,
(iii) study of immuno-modulating effects
of H-1PV to optimize its use to treat pan-
creatic carcinomas.
3. Our Virus Production & Development
Unit standardizes protocols for virus ap-
plication to humans, and supports trial-
accompanying research.
Future Outlook:
Basic research will be pursued to unravel the
cellular and parvoviral determinants of cell
permissiveness and killing, respectively. This
program is expected to contribute to identify
patients susceptible to oncolytic virus-based
treatments (customized therapy). Further-
more, our ambition is also to understand and
optimize the interplay between parvovirus
oncolytic effects and host anti-tumor immune
responses (through parvovirus arming with
chemokines or modulation of critical steps of
the viral life-cycle, in particular egress). On the
translational level, our work aims to broaden
the range of indications for a potential H-1PV-
based oncolytic virotherapy. In order to prepare
future clinical trials, besides the glioma study
already under way, optimal treatment strate-
gies combining parvoviruses with different
classes of antineoplastic and immunomodu-
lating agents will be tested, using various in
vitro and in vivo models. On the basis of prom-
ising pre-clinical data, priority will be given
to clinical validation of treatment efcacy in
pancreatic carcinoma patients and in patients
with relapsed or refractory tumors in the eld
of pediatric neuro-oncology.
ESSENTIAL PUBLICATIONS: (1.) Rommelaere J. et al.
(2010). Oncolytic parvoviruses as cancer therapeutics.
Cytokine and Growth Factor Reviews, 21, 185195. (2.)
Geletneky K. et al. (2010). Regression of advanced rat
and human gliomas by local or systemic treatment
with oncolytic parvovirus H-1 in rat models. Neuro
Oncol, 12, 804814. (3.) Sonntag F. et al. (2010). A viral
assembly factor promotes AAV2 capsid formation in
the nucleolus. Proceedings of the National Academy
of Sciences, USA, 107, 1022010225. (4.) Nesch J. et al.
(2007). A novel viral adaptor protein modulating Ca-
sein Kinase II activity induces cytopathic effects in
permissive cells. Proceedings of the National Acade-
my of Sciences, USA, 104, 1248212487.
Treatment of an
intracerebral rat glioma
with parvovirus H-1
(H-1PV). MRI of a rat brain
bearing a glioma, at the
time of infection with
H-1PV (left), and 8 days
later (right), showing
disappearance of the
tumor after infection.
Genome Modications and Carcinogenesis
Division
Head: Prof. Dr. Lutz Gissmann
Genome Modifications and Carcinogenesis
(F020)
69120 Heidelberg
Tel: +49 6221 42 46 03
E-mail: l.gissmann@dkfz.de
Since currently available vaccines against cer-
tain types of human papillomavirus (HPV) for
the prevention of cervical cancer are far from
perfect, our devision is developing second-
generation vaccines, i.e. the generation of
cheaper prophylactic vaccines, the develop-
ment of an HPV16 therapeutic DNA vaccine
for the treatment of cervical neoplasia, the
generation of an HPV16 particle-based vaccine
with combined prophylactic and therapeutic
properties and the development of a vaccine
for the prevention of skin papillomatosis in
organ transplant recipients. Our vaccine pro-
gram includes basic research to generate a
vaccine against different strains of HIV. Based
on a high-throughput platform for multiplex
detection of antibodies and nucleic acids, we
are participating in large epidemiologic trials
to evaluate the role of HPV and other microbes
in cancers for which an infectious etiology
has not yet been established. The program on
foamy viruses from different animal species
deals with their host restriction and the evalu-
ation of a possible inter-species transmission
(zoonosis) with the potential for acquiring
transforming properties in humans. We study
the role of two classes of molecules (cyclooxy-
genases and lipoxygenases) that are central in
chronic inammation which is a well-dened
risk factor for cancer development.
Future Outlook:
We plan to evaluate our candidate vaccines as
described above in clinical trials, with the aim
to develop them into commercial products.
Our high-throughput platform, suited to si-
multaneously screen for antibodies against a
variety of viruses and bacteria, will be expand-
ed to evaluate still undescribed links between
infection and cancer. These analyses will in-
clude foamy viruses to evaluate their potential
role in human cancer. The high-throughput
multiplex platform will also be used to test for
HPV-specic nucleic acids as early biomarkers
for development of cervical cancer.
ESSENTIAL PUBLICATIONS: (1.) Senger T. et al. (2010).
Virus-like particles and capsomeres are potent vac-
cines against cutaneous alpha HPVs Vaccine. Vac-
cine, 28, 15831593. (2.) Schmitt M. et al. (2010). Diag-
nosing Cervical Cancer and High-Grade Precursors
by HPV16 Transcription Patterns. Cancer Res, 70, 249
256. (3.) Dell K. et al. (2006). Intransasal immuniza-
tion with human papillomavirus type 16 capsomer-
es in the presence of non-toxic cholera toxin-based
adjuvants elicits increased vaginal immunoglobu-
lin levels. Vaccine, 24, 22382247. (4.) Schdlich L. et
al. (2009). Analysis of modied HPV 16 L1 capsomer-
es: The ability to assemble into larger particles corre-
lates with higher immunogenicity. J Virol, 83, 7690
7705.
Instrumentation for multiplex
serology and multiplex genotyping
Head: Prof. Dr. Frank Rsl
Viral Transformation Mechanisms
Division
Viral Transformation Mechanisms (F030)
69120 Heidelberg
Tel: +49 6221 42 4900
E-Mail: f.roesl@dkfz.de
1. Mechanisms of human papillomavirus
(HPV)-induced carcinogenesis: Here we are
investigating how transcription and viral RNA
splicing of high-risk HPV is regulated during
the different steps towards malignant trans-
formation. Another focus is the function of
epigenetic mechanisms (e.g. de novo methyla-
tion, nucleosomal organisation, micro-RNAs)
in HPV-positive cells and their impact on viral-
host interaction during persistence.
2. Immunological surveillance:
In this context, we are studying the interferon/
chemokine pathway to understand the innate
response against a viral infection. Moreover,
with respect to the role of inammation in
cancer, we are examining the function of indi-
vidual HPV oncoproteins on the NALP3 inam-
masome.
3. A natural rodent model system for papillo-
mavirus (PV)-induced skin cancer:
In this project we study the whole infection
pathway, starting from primary infection till
the nal manifestation of a skin tumor in mo-
lecular and serological terms. We have also
developed a virus-like particle (VLP) based
vaccine to prevent PV-induced skin lesions. This
vaccine is currently tested under normal and
immunocomprimised conditions.
4. Virus-Cell Interactome
Considering a cell as a functional regulatory
network, tumorviruses always attack central
hubs to overcome intracellular surveillance.
It is therefore necessary to understand these
viral-host interactions using both approaches
of systems biology and high-throughput strat-
egies.
Future Outlook:
Beside the current projects which will be fol-
lowed up in greater detail, we will focus our
future interest on the following topics:
1. Metabolism and cancer:
Here we will especially determine the func-
tion of the viral oncoproteins on the metabolic
pathway. We have already mapped the regula-
tory region of the LKB1 tumor suppressor gene,
a central master kinase that controls the in-
tracellular energy status. This gene is found to
be dysregulated in HPV-positive cells. We have
also dissected the mechanism how tumor cells
sense their own metabolism. We will further
analyse the innate immune response under
hypoxic and energy-deprived conditions.
2. Cellular escape mechanisms:
This study aims to understand the spatial and
temporal interaction of immunological effec-
tor cells of the innate defence system with
non-tumorigenic HPV-positive cells, in direct
comparison with their tumorigenic counter-
parts in immunocompromized animals. In ad-
dition, we design experiments that allow the
characterization of genes and intracellular reg-
ulatory pathways in transplanted HPV-positive
cells responsible for tumor suppression.
3. Resistance mechanisms:
Cancer cells are robust and highly adaptive
against various therapeutic approaches. Al-
though most of the tumor mass can be eradi-
cated in vivo and in vitro, there are still cells
which survive. Whether these represent cancer
stem cells will be studied in further detail.
ESSENTIAL PUBLICATIONS: (1.) Ltzner N. et al. (2012).
FOXO3 is a Glucocorticoid Receptor Target Gene
and Regulates LKB1 and FOXO3 Expression Depend-
ent on Intracellular Energy Levels Via a Positive Au-
toregulatory Feedback Loop. PLoS One. 7: e42166. (2.)
Rincon-Orozco B. et al. (2009). Epigenetic silencing of
interferon- in human papillomavirus type 16 posi-
tive cells. Cancer Research, 69, 87188725. (3.) Rosen-
berger S.J. et al. (2010). Alternative splicing of HPV16
E6/E6* early mRNA is coupled to EGF-signalling via
Erk activation. Proc. Natl. Acad Sci. U.S.A., 107, 7006
7011. (4.) Schfer K. et al. (2011). Serological markers
for papillomavirus infection and skin tumour devel-
opment in the rodent animal model Mastomys cou-
cha. Journal of General Virology, 92, 383394.
Mitochondria staining in primary
keratinocytes (orange).
Courtesy of Dr. B. Rincon Orozco (F030)
Characterization of Tumorviruses
Division
Head: Prof. Dr. Ethel-Michele de Villiers
Characterization of Tumorviruses (F070)
69120 Heidelberg
Tel: +49 6221 42 4655
E-Mail: e.devilliers@dkfz.de
It has not been possible to associate the ubiqui-
tous TT viruses to a specic disease entity, de-
spite initial intensive worldwide investigation.
We conducted our investigations along several
lines in order to address this problem: Serum
samples and biopsies from healthy individuals,
as well as from patients with multiple scle-
rosis, rheumatoid arthritis, colon carcinoma,
leukemia and lymphoma were analyzed for
the presence of TT virus DNA. Although TT vi-
rus DNA was present in the majority of these
samples, we demonstrated the existence of
additional intragenomic rearranged viral mole-
cules: one comprising replication-defective and
the other replication-competent episomes. The
latter consisted of as little as 10% of the origi-
nating full-length TT virus genome and was
termed TTV. We developed an in vitro replica-
tion system for these viruses in which we con-
rmed the formation and existence of TTV
molecules, along with the replication of the re-
spective full-length genomes. Intragenomic re-
arranged TT molecules, as well as in vitro tran-
scripts revealed new open reading frames of
which the putative proteins shared similarities
to signature motifs present in cellular proteins
involved in autoimmune diseases. The highly
conserved region (71 bp) of TT viruses harbor-
ing the origin of replication was demonstrated
in a spectrum of cell lines. Long distance PCR-
amplication based on this region led to the
identication of circular chimeric molecules
comprising TT virus sequences combined with
cellular sequences. A large series 0f bovine
sera was analyzed for TT sequences.
Future Outlook:
Proteins expressed by TT viral and subviral ge-
nomes are characterized and tested for a pos-
sible role in molecular mimicry through their
cross-reaction against antibodies involved in
autoimmune diseases. The mechanism un-
derlying the origin and function of cellular-TT
virus chimeric molecules is being investigated.
Specicity of the chimeric recombinant mol-
ecules for certain types of tumors and autoim-
mune diseases will be investigated. This may
then, in addition, lead to their development
and use as diagnostic markers. The origin and
function of an unusual pattern of TT virus se-
quences identied in bovine serum samples
will be analyzed, as well as possible transmis-
sion of TT virus originating from cattle (via se-
rum, saliva and milk) to humans. An intensive
search for putative new viruses involved in
tumorigenesis is continuing, with transmis-
sion from cattle to humans being the main
focus. Full-length genomes of newly identied
TT virus are being isolated and characterized
from serum samples from leukemia patients.
Development of chimeric constructs for use as
extra chromosomal vectors poses an impor-
tant challenge.
ESSENTIAL PUBLICATIONS: (1.) de Villiers E.M. et al.
(2011). The diversity of Torque teno viruses: In vitro
replication leads to the formation of additional rep-
lication-competent subviral Molecules. J Virol, 85,
72847295. (2.) zur Hausen H. (2012). Red meat con-
sumption and cancer: Reasons to suspect involve-
ment of bovine infectious factors in colorectal can-
cer. Int J Cancer. 130, 24752483. (3.) de Villiers E.-M. et.
al. (2009). Intragenomic rearrangement in TT viruses:
a possible role in the pathogenesis of disease. Curr.
Top. Microbiol. Immunol. 331, 91107. (4.) Bernard H.-U.
et al. (2010). Classication of papillomaviruses (PVs)
based on 189 PV types and proposal of taxonomic
amendments. Virology. 401, 7079.
Mechanisms under
investigation for a role of TT
viruses in the pathogenesis
of disease
Head: Prof. Dr. Dr. Henri-Jacques Delecluse
Pathogenesis of Virus Associated Tumors
Division
Pathogenesis of Virus Associated Tumors
(F100)
69120 Heidelberg
Tel: +49 6221 42 4870
E-Mail: h.delecluse@dkfz.de
The Epstein-Barr virus is etiologically linked
with 2% of all malignant tumors worldwide.
Hence, a very substantial number of cancers
could be prevented by vaccination against this
virus. Our research interests are focused on
the molecular mechanisms that allow multi-
plication, infection and ultimately, malignant
transformation of B cells and epithelial cells.
The large size of the viral genome precludes
the use of conventional cloning techniques;
instead we have developed a genetic system
that allows modication of every single base
pair within the viral genome. Over the years
we have used this technology to construct a
large panel of viral mutants that lack genes
involved in multiple virus functions. More re-
cently, we have focused our attention on viral
non-coding RNAs, such as the rst described
v-snoRNA1 or the BHRF1 microRNA cluster. A
virus that lacks all three members of this clus-
ter displays a reduced propensity to transform
B lymphocytes. Another avenue of research
is the study of EBV interactions with primary
epithelial cells. Although the virus mainly rep-
licates in these cells, they also express the viral
oncogene LMP1, suggesting links between be-
tween virus replication and epithelial transfor-
mation. We have also generated mutants that
could be potentially used as vaccines. Indeed,
these produce large amounts of viral DNA-free
virus-like particles (VLPs). These particles elicit
a strong immune response, yet have lost any
pathogenic potential.
Future Outlook:
Future projects aim at pursuing the genetic
analysis of EBV functions. In particular, we
intend to identify the members of the BHRF1
miRNA cluster responsible for the phenotypic
traits observed in the triple deletion mutant.
We also intend to expand our projects on the
molecular interactions between EBV and epi-
thelial cells.
ESSENTIAL PUBLICATIONS: (1.) Feederle R. et al.
(2009). The Epstein-Barr virus alkaline exonucle-
ase BGLF5 serves pleiotropic functions in virus repli-
cation. J Virol. , 83, 49524962. (2.) Hutzinger R. et al.
(2009). Expression and processing of a small nucle-
olar RNA from the Epstein-Barr virus genome. PLoS
Pathog.,5(8):e1000547. (3.) Busse C. et al. (2010). Ep-
stein-Barr viruses that express a CD21 antibody pro-
vide evidence that gp350s functions extend beyond
B-cell surface binding. J Virol., 84, 11391147. (4.) Feed-
erle R. et al. (2011). A Viral microRNA cluster strongly
potentiates the transforming properties of a Human
Herpesvirus. PLoS Pathog 7(2): e1001294
Primary squamous epithelial cells
infected with a recombinant Epstein-
Barr virus tagged with a GFP gene.
Oncolytic Adenoviruses
Head: PD Dr. Dirk M. Nettelbeck

Oncolytic Adenoviruses (F110)
69120 Heidelberg
Tel: +49 6221 42 4450
E-Mail: d.nettelbeck@dkfz.de
and Department of Dermatology,
The mission of our group is to translate ad-
vances in basic oncology, molecular biology
and virology research into innovative adeno-
virus cancer therapeutics. Translating the ad-
vances in basic research of recent decades into
clinical applications is one of the biggest chal-
lenges of biomedicine today. This is especially
true for the development of effective cancer
therapies. Viral oncolysis, or virotherapy, is a
new strategy for treatment of cancer by tu-
mor-selective virus infection and spread. Thus,
it implements a novel mode of cancer cell kill-
ing, namely viral cell lysis. Clinical trials have
shown that oncolytic viruses are well tolerated
in patients, but also that viruses with improved
efcacy are needed to establish virotherapy in
the clinics. We engineer oncolytic agents based
on adenoviruses, which can be rationally engi-
neered to match specic applications and also
to address the limitations of previous oncolytic
agent viruses. Our main research interest is to
design and develop new generations of onco-
lytic adenoviruses for targeted, efcient and
multimodal cancer therapy. Current projects
include (1) virus capsid engineering for tar-
geted cell entry, (2) mutation of viral genes to
enhance virus spread and (3) transgene inser-
tion for expression of therapeutic proteins to
facilitate multimodal action and anti-tumor
immune activation.
Future Outlook:
The major goals of our group for the coming
years are to implement innovative strategies
for targeted, efcient and multimodal viro-
therapy:
TARGETING: Adenovirus Capsid Engineering for
Tumor-Targeted Cell Entry. We have developed
an adenovirus capsid scaffold for the insertion
of tumor-targeting ligands. Future work will
focus on the investigation of different ligands
in this context and subsequently, on the devel-
opment of entry-targeted oncolytic adenovi-
ruses in relevant pre-clinical models.
EFFICIENCY: Enhanced Viral Lysis of Tumor
Cells. We will identify and characterize adeno-
virus mutants with enhanced oncolysis phe-
notype by rational mutagenesis and directed
evolution.
MULTIMODALITY: Therapeutic Gene Expres-
sion. On the basis of our established strategies
for tumor-targeted and efcient transgene
expression by oncolytic adenoviruses, we will
investigate combination therapies of viral
oncolysis and therapeutic protein expression
(viro-immunotherapy and viro-chemotherapy).
Moreover, we explore strategies for external
control of virus-mediated therapeutic gene ex-
pression. By implementing these strategies we
aim at dening a candidate oncolytic adenovi-
rus for clinical translation, in cooperation with
our partners at the Heidelberg University Hos-
pital and National Center for Tumor Diseases
(NCT) Heidelberg.
ESSENTIAL PUBLICATIONS: (1.) Ketzer P. et al. (2012).
Synthetic Riboswitches for External Regulation of
Genes Transferred By Replication-Decient and
Oncolytic Adenoviruses. Nucleic Acids Research,
40(21):e167. (2.) Schierer S. et al. (2011). Human Den-
dritic Cells Efciently Phagocytose Adenoviral Onco-
lysate, but Require Additional Stimulation to Mature.
Int J Cancer. 130, 168294. (3.) Quirin C. et al. (2011). Se-
lectivity and Efciency of Late Transgene Expression
by Transcriptionally Targeted Oncolytic Adenoviruses
are Dependent on the Transgene Insertion Strategy.
Human Gene Therapy, 22, 389404. With accompa-
nying commentary by Leonard W. Seymour: Onco-
lytic Virotherapy: Combining First-Rate Science with
an Unmet Clinical Need. (4.) Nettelbeck D.M. et al.
(2008). Tumor-Busting Viruses. Scientific American,
Special Edition New Answers for Cancer, 7279.
A tumor cell nodule was infected with an oncolytic
adenovirus that can be detected by production of a
green uorescent protein. On day 2, only the outer
parts of the nodule are infected. In the following
days, the virus replicates and spreads, resulting in
infection of major parts of the nodule.
Research Program 116 Research Program
Head: Dr. Grant Hansman
Noroviruses
CHS Junior Research Group (in Cooperation with
Heidelberg University)
Noroviruses (F150)
69120 Heidelberg
Tel: +49 6221 42 1520
E-Mail: g.hansman@dkfz.de
Noroviruses are now known to be the domi-
nant cause of outbreaks of gastroenteritis
around the world. Currently, there are no vac-
cines for noroviruses and cross-protection
from future norovirus infections is uncertain,
and it is not uncommon for re-infection with a
genetically similar strain. Although the disease
is self-limiting, symptoms can persist for days
or even weeks and transmission from person-
to-person is difcult to control once the out-
break has occurred.
Noroviruses are an enormous problem in
closed settings such as hospitals, nursing
homes, cruise ships and schools. Human
noroviruses are frequently associated with
food-borne outbreaks of gastroenteritis. In a
nutshell, human noroviruses are everywhere
and infect all age groups. Human noroviruses
are uncultivable, but expression of the capsid
protein in a baculovirus expression system
results in the self-assembly of virus-like parti-
cles (VLPs) that are morphologically and anti-
genically similar to the native virion. The X-ray
crystal structure of the VLP shows the capsid is
divided into two domains, shell and protruding
(P) domains. The P domain is further divided
into P1 and P2 subdomains, with the P1 subdo-
main interacting with the shell and the P2 sub-
domain residing on the outer surface of the
capsid and likely containing the determinants
for receptor binding and antigenicity.
The human histo-blood group antigens
(HBGAs) have been identied as potential
co-factors for norovirus. A number of crystal
structures have been determined for HBGAs
in complex with P domains. Our group plans
to express a panel of norovirus strains in order
to better understand the interactions with the
polymorphic HBGAs.
Recently, we analyzed the interaction of citrate
with GII noroviruses using X-ray crystallogra-
phy and saturation transfer difference (STD)
NMR. We found that the citrate interaction
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was coordinated with an almost identical set
of capsid interactions involved in recogniz-
ing the terminal HBGA fucose, the saccharide
which forms the primary conserved interaction
between HBGAs and GII noroviruses. STD NMR
showed the protruding domain to have weak
afnity for citrate, but could compete against
the soluble HBGAs for the HBGA binding site.
Our group plans to screen other candidate
drug molecules that bind and inhibit norovirus
attachment to cells.
We recently solved the cryo-EM structure of
the non-infectious GII.10 VLPs and found that
the overall capsid structure was very similar to
the murine norovirus virion, including raised
and rotated P domains. Surprisingly, for over
12 years, the prototype GI.1 human norovirus
VLP was considered a good representative for
all human norovirus capsid structures and the
same group later demonstrated this with the
structure of a GII.4 human norovirus VLP. The
analysis of the GII.10 VLP cryo-EM structure
indicated that the norovirus capsid was ex-
tremely exible and this exibility could be the
underlying basis for receptor binding and anti-
body specicity. Our group plans to determine
the structures of other human norovirus VLPs
in order to describe the extent of the structural
diversity and to better understand capsid ex-
ibility.
ESSENTIAL PUBLICATIONS: (1.) Hansman G.S. et al.
(2012). Structural basis for broad detection of geno-
group II noroviruses by a monoclonal antibody that
binds to a site occluded in the viral particle. J Virol.,
86, 36353646. (2.) Hansman G.S. et al. (2012). Struc-
tural basis for norovirus inhibition and fucose mim-
icry by citrate. J Virol., 86, 284292. (3.) Hansman G.S.
et al. (2011). Crystal Structures of GII.10 and GII.12
Norovirus Protruding Domains in Complex with His-
to-Blood Group Antigens Reveal Details for a Poten-
tial Site of Vulnerability. J Virol., 85, 66876701. (4.)
Ozawa K et al. (2007). Norovirus infections in symp-
tomatic and asymptomatic food handlers in Japan. J
Clin Microbiol., 45, 39964005.
Foundation (CHS). Schematic
representation
of norovirus
Infection and Innate Immune Sensing Dynamics
Head: Dr. Steeve Boulant
Infection and Innate Immune Sensing
Dynamics (F140)
69120 Heidelberg
Tel: +49 6221 42 1560
E-Mail: s.boulant@dkfz.de
The laboratory is interested in the spatio-
temporal aspects of viral infection. We use
viruses as a model system to understand cel-
lular mechanisms, from entry of viral particles
and intracellular trafcking to antiviral innate
immune response. We mainly use reovirus, a
small non-enveloped virus prototype for the
Reoviridae family, which contains the medi-
cally important virus Rotavirus.
We use a combination of live-cell confocal
uorescent microscopy and single particle
tracking to dissect the mechanisms by which
viruses are probed within the infected host. We
have developed, and continue to develop, uo-
rescent tools that allow us to track individual
viral particles within a living cell, from entry
and translocation into the cytosol of the host
to recognition by the innate immune system.
The laboratory is particularly interested in
how viruses enter polarized intestinal epithe-
lial cells (IECs) and how these cells respond
to pathogen infection. IECs constitute the
primary barrier that pathogens have to pass
to establish infection originating in the gut.
Polarized cells have developed a unique strat-
egy to regulate intracellular trafcking to
maintain polarity. Indeed, despite being in con-
stant contact with the commensal bacterial
and viral ora, IECs in physiological conditions
do not generate a constant pro-inammatory
response. As such, IECs have developed unique
strategies to tolerate the commensal microbial
ora and, at the same time, to efciently pro-
tect against pathogens.
Virus Entry
Reovirus enters cells by clathrin-mediated en-
docytosis after binding to the tight junction
protein Jam-A and 1 integrin. Our goal is to
characterize how viruses attach to their recep-
tors and whether this interaction promotes
their active uptake by the cell. We are particu-
larly interested in the molecular aspects that
allow the coupling of the viral particles to the
endocytic machinery.
Anti-viral innate immune response
Results show that IECs can generate a differ-
ent qualitative/quantitative innate immune
response upon viral infection, depending on
where the infection originates (apical vs baso-
lateral). Our goal is to elucidate the molecular
mechanisms that differentially regulate innate
immune response in polarized epithelial cells
infected by viruses. Ultimately, we aim to un-
derstand how the innate immune response in
the intestine is regulated to maintain colonic
homeostasis.
ESSENTIAL PUBLICATIONS: (1.) Boulant S. et al. (2011).
Actin dynamics counteract membrane tension dur-
ing clathrin-mediated endocytosis. Nat Cell Biol, 13,
11241131. (2.) Cocucci E. et al. (2012). The rst ve sec-
onds in the life of a clathrin-coated pit. Cell, 150, 495
507. (3.) Boulant S. et al. (2011). Recruitment of cellular
clathrin to viral factories and disruption of clathrin-
dependent trafcking.Traffic, 12, 11791195. (4.) Dix-
it E. et al. (2010). Peroxisomes are signaling platforms
for antiviral innate immunity. Cell, 141, 668681.
Foundation (CHS).
Head: PD Dr. Dr. Angelika Riemer
Immunotherapy and Prevention
Immunotherapy and Prevention (F130)
69120 Heidelberg
Tel: +49 6221 42 3820
E-Mail: a.riemer@dkfz.de
At least 20% of human malignancies are
caused by consequences of persistent infec-
tions. Cancers caused by infectious agents
(e.g. human papillomavirus HPV) are attrac-
tive targets for cancer vaccination approach-
es, as they provide the opportunity to target
antigens that are immunologically non-self.
Vaccination can be prophylactic, inducing an-
tibodies that prevent infection, or therapeutic,
stimulating the cellular immune system into
eradicating established disease. Prophylac-
tic immunization against HPV has become
the paradigm for cancer immunoprevention.
Unfortunately, current HPV vaccines have no
therapeutic effect on existing infections. The
aim of therapeutic vaccination is to stimulate
the immune system into recognizing and de-
stroying malignant cells. Cytotoxic T cells (CTL)
kill infected cells after recognizing bits of viral
proteins, so-called epitopes, which are present-
ed on human leukocyte antigen (HLA) mol-
ecules on the cell surface. There are thousands
of different HLA types, all presenting different
epitopes. As every human being has a differ-
ent set of HLA molecules, epitopes for all major
HLA groups need to be dened. The overall
aim of this group is to generate a therapeutic
cancer vaccine against HPV-induced malignan-
cies that is applicable to everyone, regardless
of a persons HLA type. We are currently work-
ing on the precise identication of which HPV
epitopes are present on tumor cells using a
specialized mass spectrometry (MS) approach.
Future Outlook:
As nearly every sexually active individual ac-
quires a high-risk HPV infection during their
lifetime, but only 1-2% develop persistent
infection, there must be differences in the in-
duction of effective immune responses. It has
been shown that local inammatory cytokines
are needed for the generation of anti-HPV ef-
fector T cells. We therefore plan to investi-
gate differences in the inammatory status
of early HPV-induced lesions between people
who mount effective immune responses and
those who do not. Since T helper cells are also
crucially involved in HPV clearance, another
project deals with the identication of natu-
rally processed promiscuous HPV-derived HLA-
class-II epitopes. The inclusion of such epitopes
in therapeutic vaccine formulations is likely
to enhance their efcacy. Future aims are to
examine various vaccine delivery and adjuvant
formulations. All these studies will contrib-
ute to an optimal formulation of a therapeu-
tic vaccine, aiming at the effective induction
of adaptive immune responses in persistently
HPV-infected patients. The developed technol-
ogy could then be applied to more high-risk
HPV types, but also to low-risk types which are
causing signicant morbidity. If this approach
using an epitope-specic, yet widely applica-
ble, therapeutic vaccine is successful, it may be
further developed into a platform technology
against other malignancies. Insights gained
during this process may be used in the further
development of cancer vaccinology.
ESSENTIAL PUBLICATIONS: (1.) Riemer A.B. et al. (2010).
A conserved E7-derived CTL epitope expressed on hu-
man papillomavirus-16 transformed HLA-A2+ human
epithelial cancers. J. Biol. Chem., 285, 2960829622.
(2.) Anderson K.S. et al. (2011). Impaired tumor anti-
gen processing by immunoproteasome-expressing
CD40-activated B cells and dendritic cells. Cancer Im-
munol. Immunother., 60, 857867. (3.) Riemer A.B. et
al. (2005). Vaccination with cetuximab mimotopes
and biological properties of induced anti-EGFR anti-
bodies. J. Natl. Cancer Inst., 97, 16631670. (4.) Riemer
A.B. et al. (2004). Generation of peptide mimics of the
epitope recognized by trastuzumab on the oncogenic
protein Her-2/neu. J. Immunol., 173, 394401.
Human Papillomavirus (HPV)
Translational Cancer
Research
The Research Program is composed of the Divisions of Translational
Oncology and Preventive Oncology, which are both located at the
National Center for Tumor Diseases (NCT) Heidelberg and equipped
by the DKFZ. Further components of the Research Program are the
Clinical Cooperation Units, which are operated jointly with the Me-
dical Faculties of Heidelberg and Mannheim, and further divisions
and working groups of the DKFZ engaged in translational research.
The Research Program has three major goals:
1. Supporting the excellent preclinical research of the DKFZs
translational research portfolio.
2. Offering centralized services for the effective preparation and
realization of investigator initiated trials and basic research
projects with patient material.
3. Facilitating, via the Departments of Medical Oncology and
Translational Oncology funded jointly with Heidelberg Univer-
sity Hospitals, patient access for systematic clinical implemen-
tation of phase I to IV trials.
Great importance is attached to creating solid infrastructure
conditions, e.g. by obtaining patient material by systematic tumor
and serum banking (biobanking), developing regulatory clinical
protocols by trial physicians and validated laboratory investigations
accompanying trials as well as biostatistical support and evaluati-
on. The goal is also to speed up implementation in clinical research
by overcoming the greatest obstacles arising from the laboratory
workbench to the hospital bed.
Coordinator
Prof. Dr. Christof von Kalle
120 Research Program
Head: Prof. Dr. Christof von Kalle
Translational Oncology
Division
Translational Oncology (G100)
69120 Heidelberg
Tel: +49 6221 56 6990
E-Mail: christof.kalle@NCT-Heidelberg.de
The division of Translational Oncology, lead
by Christof von Kalle, coordinates all major
aspects of creating and growing NCT and the
translational research topics of DKFZ. The re-
search program of the department focuses
on the genetic diagnosis and modication
of stem cell populations in cancer and other
genetic diseases. Comprehensive mechanistic
analysis of clonal dominance and proprietary
high-throughput genomics are used to study
the cellular and molecular mechanisms of
disease initiation, progression and metastasis
formation of cancer initiating cells, as well as
equivalent mechanisms in leukemia, aiming
at identication of new therapeutic targets.
Molecular studies focus on mutations in inher-
ited and acquired genetic diseases, including
cancer, and serve as the basis of virus-derived
therapeutics to treat them. This work has led
the eld internationally in important aspects
of gene therapy, and has pioneered mechanis-
tic investigations of vector integration using
state-of-the-art high-throughput genomics
and bioinformatics. The devision guides the
development of the NCT Precision Oncology
Program (NCT POP), which aims to provide a
comprehensive high-throughput molecular
and cellular analysis of every patient treated
at NCT, leading to therapeutic stratication ac-
cording to specic molecular and cellular tar-
gets found in their individual tumors.
Future Outlook:
The division of Translational Oncology will fur-
ther develop its research program focus in the
eld of normal and cancerous stem cell biolo-
gy, insertional mutagenesis in cancer and gene
therapeutic approaches. It aims to decipher
mechanisms of tumor initiation, self-renewal,
metastasis and heterogeneity of tumor-initiat-
ing cells and of the step-wise malignant trans-
formation in leukemogenesis. The division
drives the development of NCT Precision On-
cology Program (NCT POP) that aims at strati-
cation of cancer patients based on molecular
alterations, aimed at targeted treatment ap-
proaches and hypothesis-driven interventional
trials. Structural and functional genomics and
innovative treatment approaches target indi-
vidual genetic lesions. Future clinical studies
will include real-time high-throughput clonal
monitoring of the T-lymphocyte repertoire in
immunotherapy and of gene corrected cells.
New vector systems allowing either reduced
integration efciency (integrase-decient
lentiviral vectors) and/or targeted integra-
tion in specic safe genomic locations (zinc
nger nucleases) are being developed. Eluci-
dation of genomic instability and the role of
double-strand breaks in carcinogenesis are
rapidly growing direct extensions of this work.
Functional genomics studies aim at new thera-
peutic strategies breaking therapy resistance
in high risk chronic lymphocytic leukemia. Fur-
thermore, second-generation measles virus for
oncolytic therapy will be tested with the objec-
tive of phase I clinical trial development.
ESSENTIAL PUBLICATIONS: (1.) Dietrich S. et al. (2012).
BRAF inhibition in refractory hairy-cell leukemia.
N Engl J Med, 366, 20382040. (2.) Dieter SM. et al.
(2011). Distinct types of tumor-initiating cells form
human colon cancer tumors and metastases. Cell
Stem Cell, 9, 357365. (3.) Gabriel R. et al. (2011). An
unbiased genome-wide analysis of zinc-nger nucle-
ase specicity. Nature Biotech, 29, 816823. (4.) Stein
S. et al. (2010). Genomic instability and myelodyspla-
sia with monosomy 7 consequent to EVI1 activation
after gene therapy for chronic granulomatous dis-
ease. Nat Med, 16, 198204.
Bone marrow inltration,
as determined by
immunohistochemical
staining for CD20 (top of
panel A), was 70% before
vemurafenib treatment and
cleared with treatment. The
size of the hairy-cell leukemia
clone in the peripheral
blood, as assessed by
immunophenotyping (CD20
and CD103) (bottom of panel
A), decreased rapidly with
vemurafenib treatment.
Applied Tumor Biology
Head:
Prof. Dr. Magnus von Knebel Doeberitz
Applied Tumor Biology (G105)
69120 Heidelberg
Tel: +49 6221 42 2487
E-Mail: knebel@med.uni-heidelberg.de
The Clinical Cooperation Unit Applied Tumor
Biology is a clinical research cooperation unit
with the Department of Applied Tumor Biol-
ogy of Heidelberg University Hospitals and is
part of the Molecular Medicine Partner Unit
of the European Molecular Biology Laboratory
(EMBL). Our major scientic interests relate to
mechanisms of genomic instability triggered
by human papillomavirus infections and DNA
mismatch repair deciency. We aim to iden-
tify novel diagnostic markers and potential
therapeutic targets. We design and organize
clinical trials, in cooperation with several clini-
cal partners, to validate the clinical impact of
respective markers and targets. We further
successfully established spin off companies
to guarantee the clinical translation of scien-
tic concepts into commercially available certi-
ed products. Examples of diagnostic markers
developed by our group are p16INK4a and
the CINtec product line used as diagnostic
markers for HPV-induced lesions in histo- and
cytopathology, that within a few years have
become the new global gold standard in the
diagnostics of HPV-associated neoplasms. We
further developed a novel immune surveil-
lance concept for DNA mismatch repair de-
cient cancers that led to the development of
vaccines presently being tested in clinical tri-
als. Current research activities of our group are
focussing further on the epigenetic regulation
of human papillomavirus infections.
ESSENTIAL PUBLICATIONS: (1.) von Knebel Doeberitz
M. et al. (2012). Biomarkers for cervical cancer screen-
ing: the role of p16(INK4a) to highlight transform-
ing HPV infections. Expert Rev Proteomics,9 ,149163.
(2.) Reuschenbach M. et al. (2012). Evaluation of cer-
vical cone biopsies for coexpression of p16INK4a and
Ki-67 in epithelial cells. Int J Cancer, 130, 388394. (3.)
Kloor M. et al. (2012). Prevalence of mismatch repair-
decient crypt foci in Lynch syndrome: a pathological
study. Lancet Oncol, 13, 598606. (4.) Kloor M. et al.
(2011). Analysis of EPCAM protein expression in diag-
nostics of Lynch syndrome. J Clin Oncol, 29, 223227.
Example for HPV transformed cells
in histology (a and c) and cytology
(b and d) specimens stained for
p16INK4a (a & c) and p16INK4a
and Ki67 (b & d). Co-expression
of both markers unequivocally
indicates transformation of these
cells even in a cytology sample.
This results in a substantially
better reproducible and more
sensitive and specic identication
of HPV-associated pre-cancer
cells,thus helping to overcome
most limitations of current cervical
cancer early detection programs.
Head: Prof. Dr. Cornelia Ulrich
Preventive Oncology
Division
Preventive Oncology (G110a)
69120 Heidelberg
Tel: +49 6221 56 5230
E-Mail: n.ulrich@dkfz.de
The division of Preventive Oncology reduces
the burden of cancer by conducting cutting-
edge research in three areas, (a) primary pre-
vention (identication of risk factors and bio-
logic mechanisms), (b) secondary prevention
(early detection and screening), and tertiary
prevention (improving clinical outcomes of
cancer patients). Using state-of-the-art meth-
ods, including coordinated -omic strategies in
high quality observational and intervention
studies, we explore molecular pathways of risk
and clinical outcome. Targets are high-impact
areas including energy balance/adipose-tis-
sue/metabolic syndrome, inammatory/im-
mune-modulatory processes, and lifestyle/mi-
crobial communities. Pioneering work focuses
on genetically-targeted, personalized preven-
tion strategies through highly effective non-
steroidal anti-inammatory drugs.
We collaborate closely with many colleagues at
the Heidelberg University Clinic to dene novel
predictive and prognostic markers among
cancer patients and to discern health behav-
iors with major impact on cancer prognosis. In
uniquely designed clinical trials we test exer-
cise as an adjuvant therapy in cancer and di-
rectly translate our ndings into the clinic and
population. Among other research initiatives,
we lead the interdisciplinary ColoCare Study in
Heidelberg as part of an international consorti-
um with the Fred Hutchinson Cancer Research
Center in Seattle and the Moftt Cancer Center
in Tampa. The study builds on a cohort of colo-
rectal cancer patients and has as its main aim
the improvement of prognosis among colorectal
cancer patients through modiable health be-
haviors as well as molecularly tailored therapies.
Future Outlook:
The most important goals of our division are
to advance cancer prevention by identifying
molecular mechanisms and developing strat-
egies for personalized cancer prevention. In
addition, we strive to develop evidence-based
guidelines on health behavior interventions
after cancer diagnosis. We apply state-of-the
art methods in epidemiologic studies, devis-
ing new strategies for the statistical pathway
analysis. Our approach is interdisciplinary in
collaborating extensively with other groups
and consortia. One particularly interesting
new research area addresses the obesity epi-
demic, its impact on inammatory processes
and, in consequence, on cancer development.
In a large cohort of colorectal cancer patients,
we will address this topic on multiple interre-
lated levels: We will investigate the inuence
of gene-expression and proteome patterns
of tumor-adjacent adipose tissue on the mo-
lecular characteristics of colorectal tumors,
with a special focus on inammation and
angiogenesis. Clinicopathological and mo-
lecular tumor characteristics are investigated
in relation to the patients systemic status of
inammation and oxidative damage, and to
physiologic characteristics (e.g., amount, type,
and distribution of body fat) and to health
behaviors (e.g., exercise training/sedentari-
ness, and sun exposure). Through these in-
tegrated, interdisciplinary investigations, we
expect to gain novel insights into molecular
pathways. By identifying in these multilevel
investigations the factors that matter most
in cancer progression, we can derive the most
effective, targeted prevention strategies.
ESSENTIAL PUBLICATIONS: (1.) Ulrich C.M. et al.
(2007). Non-steroidal anti-inammatory drugs for
cancer prevention: promise, perils and pharmacoge-
netics. Nature Reviews Cancer, 6, 130140. (2.) Pierce
B.L. et al. (2009). Elevated biomarkers of inamma-
tion are associated with reduced survival among
breast cancer patients. Journal of Clinical Oncolo-
gy, 27, 34373444. (3.) Wiskemann J. et al. (2011). Ef-
fects of a partly self-administered exercise program
before, during and after allogeneic stem cell trans-
plantation. Blood, 117, 26042613. (4.) Imayama I. et
al. (2012). Effects of a caloric restriction weight loss
diet and exercise on inammatory biomarkers in
overweight/obese postmenopausal women: a rand-
omized controlled trial. Cancer Res, 72, 23142326.
As part of our interventions studies
among hematopoietic stem-
cell transplantation patients we
demonstrated that physical exercise
signicantly reduced cancer-related
fatigue (Wiskemann et al. 2011, Blood).
Cellular and Molecular Pathology
Division
Head: Prof. Dr. Hermann-Josef Grne
Cellular and Molecular Pathology (G130)
69120 Heidelberg
Tel: +49 6221 42 4350
E-Mail: h.-j.groene@dkfz.de
The division performs research into the cel-
lular and molecular mechanisms underlying
rejection reactions in malignant tumors and
transplanted solid organs. Rejection reac-
tions are regularly mounted by the organism
to defend itself against tumors. Using organ
transplants as animal models we can observe
the course and characteristics of rejection un-
der dened conditions. Our interest is focused
on monocytes/macrophages inammation-
promoting immune cells of the recipient and
their main target, the endothelial cells lining
the inside of the blood vessels of donor organs.
Two main groups of substances are studied
with regard to the function of monocytes/
macrophages, of endothelia and of parenchy-
mal or tumor cells in rejection: lipid-activated
nuclear receptors and glycosphingolipids (GSL).
Our goal is to gain a better understanding of
the processes underlying tissue rejection and
to transfer these ndings to tumor rejection.
This may lead to novel diagnostic methods and
treatment relating to tumor rejection. The divi-
sion is also concerned with clinical surgical pa-
thology and has established a reference center
for renal diseases. Additionally, the depart-
ment provides a service for histophathology of
tissue samples, including tissues from animal
experiments. The department is funded by the
DFG (German Research Foundation) for specic
projects and is part of concerted research ac-
tivities of the DFG.
Future Outlook:
Lipid-dependent transcription factors: Non-
steroid nuclear receptors such as retinoic acid
receptors (RARs), are activated by lipid ligands;
they have highly signicant and long lasting
effects on lipid and carbohydrate metabolism
and on the immune system. We have been
able to show that RAR- and LXR-receptors can
potently inhibit chronic brosing inamma-
tion, mainly by an effect on macrophages.
By use of specic synthetic ligands and gene
knock out mice we are analyzing the cellular
and molecular pathways by which these tran-
scription factors inuence chronic brosing
inammation. Sphingolipids and glycosphin-
golipids: Membranes of all mammalian cells
contain - in addition to phosphoglycerolipids
and cholesterol-sphingolipids: i.e. sphingomy-
elins (SM) and glycosphingolipids. These sphin-
golipids are expressed in a cell type- and differ-
entiation stage- specic manner. GSL inuence
neuronal, metabolic and immune functions.
Interactions between glycoproteins and GSLs
are pivotal to stabilize the brain and protect it
against immune reactions. We have shown in
a cell specic ganglioside-decient animal that
GSL are needed for an orderly differentiation
of non immune cells and T-lymphocytes. We
are currently using inducible cell specic knock
outs of GSL to further dene the differentia-
tion- and immune-activity of GSL.
ESSENTIAL PUBLICATIONS: (1.) von Toerne C. et al.
(2012). Modulation of Wnt and Hedgehog signaling
pathways is linked to retinoic acid-induced ameliora-
tion of chronic allograft dysfunction. Am J Transplant,
12, 5568. (2.) Traykova-Brauch M. et al. (2008). An ef-
cient and versatile system for acute and chron-
ic modulation of renal tubular function in transgen-
ic mice. Nat. Med., 14, 979984. (3.) Porubsky S. et al.
(2007). Normal development and function of invari-
ant natural killer T cells in mice with isoglobotrihex-
osylcermide (iGb3) deciency. Proc. Natl. Acad. Sci. U
S A., 104, 59775982. (4.) Schaefer L. et al. (2005). The
matrix component biglycan is proinammatory and
signals through Toll-like receptors 4 and 2 in mac-
rophages. J. Clin. Invest., 115, 22232233.
Neurons, isolated from hippocampus. Neurons
lacking GSLs show reduced dendritic processes
and early pruning (right slide).
Head: Prof. Dr. Wilfried Roth
Molecular Tumor Pathology
Molecular Tumor Pathology (G150)
69120 Heidelberg
Tel: +49 6221 56 4174
E-Mail: W.Roth@dkfz.de
Our group is located both at the DKFZ and the
Institute of Pathology at the University Hos-
pital Heidelberg. Our cooperative unit aims at
bringing together basic cancer research and
clinical medicine. In this regard, the trans-
lational research is focussed on the primary
human cancer tissue. We are specically inter-
ested in the molecular mechanisms of therapy
resistance in malignant tumors. Defects in the
intracellular signaling cascades resulting in cell
death are responsible for the therapy resist-
ance in many types of cancer. Our research is
focussed on the molecular mechanisms which
allow tumor cells to evade apoptotic or non-
apoptotic cell death. The identication of these
resistance mechanisms is a prerequisite for
the development of novel, effective therapy
approaches and contributes to a better under-
standing of the molecular basis of therapy re-
sistance in colon cancer, urological tumors, and
malignant brain tumors. The second area of
research is the identication of prognostic and
predictive tumor markers. Due to their central
biological relevance, cell death-regulating pro-
teins are decisive for the therapy response in
cancer. Therefore, we study the expression of
cell death-regulating proteins in the primary
human cancer tissue to identify tumor mark-
ers. This predictive approach in molecular
pathology aims at the identication of bio-
markers which is required for the development
of individualized therapeutic approaches for
cancer patients.
Future Outlook:
Regarding our rst research area, the mecha-
nisms of therapy resistance in cancer, we are
working on the following projects:
Functional characterization of a novel
type of cell death: giant mitochondria-
associated cytotoxicity by the HMGB1
protein.
Role of Bcl-2 family proteins for the resist-
ance to cell death in colon carcinomas.
Apoptosis resistance by the stem cell fac-
tor Notch in glioblastomas.
Regulation of cell death by miRNAs.
Mechanisms of therapy resistance in re-
nal cell carcinomas mediated by defects
in the mTOR signaling pathway.
Functional relevance of alternative types
of cell death for therapy resistance: necro-
sis and autophagy.
Regarding our second research area, the identi-
cation of tumor markers, we will focus on the
following projects:
Prognostic relevance of death ligands and
death receptors in renal cancer.
Expression and prognostic relevance of
apoptosis-regulating proteins in colon
cancer.
G proteins as novel biomarkers in malig-
nant brain tumors.
ESSENTIAL PUBLICATIONS: (1.) Gdynia G. et al. (2010).
Danger signaling protein HMGB1 induces a distinct
form of cell death accompanied by formation of gi-
ant mitochondria. Cancer Research, 70, 85588568.
(2.) Bck B.C. et al. (2010). The PEA-15 protein regu-
lates autophagy via activation of JNK. J Biol Chem,
285, 2164421654. (3.) Macher-Goeppinger S. et al.
(2009). Prognostic value of Tumor Necrosis Factor-Re-
lated Apoptosis-inducing ligand (TRAIL) and TRAIL re-
ceptors in renal cell cancer. Clinical Cancer Research,
15, 650659. (4.) Tagscherer K.E. et al. (2008). Apop-
tosis-based treatment of glioblastoma with ABT-737,
a novel small molecule inhibitor of Bcl-2 family pro-
teins. Oncogene, 27, 66466656.
Electron microscopy of a cancer cell:
Formation of giant mitochondria during the
process of a specialized form of cell death.
Dermato-Oncology
Head: Prof. Dr. Jochen Utikal
Dermato-Oncology (G300)
69120 Heidelberg
Tel: +49 621 383 4461
E-Mail: j.utikal@dkfz.de
The Clinical Cooperation Unit Dermato-Oncol-
ogy is engaged in the prevention, diagnosis,
and therapy of skin tumors. Research results
obtained are transferred directly into clinical
practice. The main focus is malignant melano-
ma, a tumor that originates from the pigment
cells of the skin. The Clinical Cooperation Unit
conducts several Phase I-III clinical trials with
innovative melanoma therapies such as MEK
inhibition or anti-CTLA4 therapy. In addition,
researchers at the department are investigat-
ing the mechanisms causing the aggressive
tumor to become resistant to chemotherapy.
Departmental researchers in basic science are
currently investigating melanoma immuno-
suppressive mechanisms and new immuno-
therapies, using a ret transgenic mouse model
that resembles human melanoma regarding
histopathology and clinical development. The
Clinical Cooperation Unit Dermato-Oncology
is part of the research program Translational
Cancer Research and is associated with the
program Tumor Immunology.
Future Outlook:
The Clinical Cooperation Unit Dermato-Oncol-
ogy will be engaged in the prevention, diag-
nosis and therapy of skin tumors, such as the
malignant melanoma. Also, different clinical
trials to improve the therapeutic options for
the treatment of this tumor type will be con-
ducted. In future an additional major focus
of the department will be stem cell research.
Embryonic stem cells and tumor cells have
many aspects in common, including immor-
tal cell growth and the potential of forming
tumors. Furthermore, melanoma cells can be
transformed via ectopic expression of these
transcription factors into a pluripotent state.
The mechanism behind this plasticity will be
studied. In addition, we plan to study the reac-
tion of the immune system towards the plas-
ticity of different melanoma subpopulations.
Accordingly, immune cells, such as myeloid
derived suppressor cells, regulatory T cells and
tolerogenic dendritic cells, will be studied in
human melanoma lesions and our ret trans-
genic mouse melanoma model. Metabolic and
signaling pathways in immunosuppressive
cells, responsible for the production of media-
tors blocking anti-tumor activity of effector
and memory T cells, will also be examined.
ESSENTIAL PUBLICATIONS: (1.) Utikal J. et al. (2009).
Immortalization eliminates a roadblock during the
reprogramming of somatic cells into iPS cells. Na-
ture., 460, 11451148. (2.) Utikal J. et al. (2009). Sox2
is dispensable for the reprogramming of melano-
cytes and melanoma cells into induced pluripotent
stem cells. J Cell Sci., 122, 35023510. (3.) Meyer C. et al.
(2011). Chronic inammation promotes myeloid-de-
rived suppressor cell activation blocking antitumor
immunity in transgenic mouse melanoma model.
Proc Natl Acad Sci U S A.; 108, 1711117116. (4.) Flaherty
K.T. et al. (2012). Improved Survival with MEK Inhibi-
tion in BRAF-Mutated Melanoma. N Engl J Med, 367,
107114. Primary malignant melanoma
Head: Prof. Dr. Alwin Krmer
Molecular Hematology/Oncology
Molecular Hematology/Oncology (G330)
69120 Heidelberg
Tel: +49 6221 42 1440
E-Mail: a.kraemer@dkfz.de
Numerical and structural chromosomal al-
terations and chromosomal instability are
common features of human malignancies. In
addition, intratumoral genetic heterogeneity
and clonal evolution are major contributors
to disease progression, relapse and treatment
resistance. Despite chromosomal instability
appears to be a major cause of tumor devel-
opment and progression, only little is known
about its molecular origins. The Clinical Coop-
eration Unit Molecular Hematology/Oncology
is studying the molecular mechanisms respon-
sible for the induction of chromosomal insta-
bility and clonal evolution in malignant neo-
plasias. One reseach topic focuses on causes
and consequences of amplied centrosomes
the spindle pole organizers responsible for
correct chromosome segregation during mito-
sis in human malignancies. Another current
topic centers around whole-genome sequenc-
ing approaches, aiming at the identication of
mutations responsible for chromosomal insta-
bility in human acute myeloid leukemias with
complex aberrant karyotypes and extremely
poor prognosis.
As major contributions, the department has
shown that both chromosomal instability and
clonal evolution is associated with disease
progression and poor prognosis in myeloid ma-
lignancies. Mechanistically, novel components
of the centrosome replication machinery have
been identied and mechanisms of normal
centrosome replication and centrosome am-
plication in cancer cells and after DNA dam-
age have been elucidated. Also, researchers
from the group together with the Translational
Oncology department (von Kalle) have dem-
onstrated that activation of the transcription
factor EVI1 causes chromosomal instability and
induces myeloid leukemias via amplication
of centrosomes. In addition, whole-genome
siRNA screening enabled them to identify the
mechanisms leading to clustering of super-
numerary centrosomes into two functional
spindle poles in cancer cells and thereafter to
target centrosomal clustering as a novel anti-
cancer strategy. Small molecule screening led
to the identication of compounds that inhibit
centrosomal clustering and selectively kill can-
cer cells with supernumerary centrosomes.
Generally, the aim of the departments research
is to better understand the processes leading
to chromosomal instability and, consequently,
to tumor development and progression. A fur-
ther goal is to exploit the results of this work
for establishing new ways of tumor classica-
tion and treatment.
ESSENTIAL PUBLICATIONS: (1.) Vulprecht J. et al. (2012).
STIL is required for centriole duplication in human
cells. J Cell Sci., 125, 13531362. (2.) Raab M.S. et al.
(2012). GF-15, a novel inhibitor of centrosomal cluster-
ing, suppresses tumor cell growth in vitro and in vi-
vo. Cancer Res., 72, 53745385. (3.) Leber B. et al. (2010).
Proteins required for centrosome clustering in can-
cer cells. Sci. Transl. Med., 2, 33ra38. (4.) Stein S. et
al. (2010). Genomic instability and myelodysplasia
with monosomy 7 consequent to EVI1 activation af-
ter gene therapy for chronic granulomatous disease.
Nat. Med., 16, 198204.
Multipolar cell division
Pediatric Oncology
The goal of the Clinical Cooperation Unit (CCU)
Pediatric Oncology is to advance the therapy
for children and adolescents with neural
cancers. Since epigenetic regulation of gene
expression is a key mechanism in stem cell
biology, differentiation and development, it is
likely that aberrant epigenetic programs play
a particular role in the genesis and progres-
sion of undifferentiated pediatric cancers.
Epigenetic programs are reversibly controlled
by an array of enzymes, including the family of
histone deacetylases (HDACs). Understanding
the molecular biology and selective target-
ing of individual HDACs of pediatric neural
cancer cells, including cancer stem cells, is
one of the central molecular concepts of the
CCU Pediatric Oncology. Our research groups
headed by Hedwig Deubzer, Ina Oehme and Till
Milde have identied particular HDAC family
members controlling differentiation, cell sur-
vival mechanisms, developmental pathways
and self renewal in neuroblastoma and brain
tumors. As a consequence, we are now devel-
oping small molecule compounds specically
inhibiting distinct HDACs for therapeutic pur-
poses in collaboration with pharma partners.
A second research focus concerns the devel-
opment of individualized, molecular based
targeted treatment concepts from patient to
bench and back. Finally, we translate our exper-
imental ndings into clinical practice through
development of individual targeted treatment
protocols for children and adolescents with
relapsed cancers, as well as conducting phase
I-III clinical trials in pediatric oncology based
on rational molecular concepts.
Future Outlook:
1. Drug target validation: We will dene the
tumor biological function of individu-
al HDACs with respect to regulation of
the human acetylome and downstream
pathways including miRNAs. To this end
we will include primary tumor material,
cancer stem cell and animal models in our
projects. This will facilitate the identica-
tion of potential biomarkers for treat-
ment response prediction and establish
the basis for patient selection in future
trials involving selective HDAC inhibitors.
2. Drug development: We will pursue the
development of selective small molecule
HDAC-inhibitors towards phase I clinical
trials. In addition, we aim for identica-
tion of synthetic lethal interacting path-
ways cooperating with selective HDAC in-
hibitors to facilitate rational combination
therapies in the future.
3. Disease models: We will extend our pri-
mary neurosphere tissue bank. We will
evaluate individualized targeted treat-
ment concepts using primary brain tumor
models and integrative genomic ap-
proaches. The ability of in vitro 3D culture
systems to predict treatment response in
vivo will be evaluated.
4. Clinical trials: We run early phase I and II
clinical trials involving HDAC inhibitor
Vorinostat in children with relapsed can-
cer. In addition, we will set up the national
phase III trial protocol and reference cent-
er for children with low grade gliomas.
ESSENTIAL PUBLICATIONS: (1.) Deubzer H. et al. (2012).
HDAC11 is a novel drug target in carcinomas. Int J
Cancer, in press. (2.)Milde T. et al. (2010). HDAC5 and
HDAC9 in medulloblastoma: novel markers for risk
stratication and role in tumor cell growth. Clin Can-
cer Res, 16, 32403252. (3.) Oehme I. et al. (2009). His-
tone deacetylase 8 in neuroblastoma tumorigene-
sis. Clin Cancer Res 5, 9199. (4.) Witt O. et al. (2009).
HDAC family: What are the cancer relevant targets?
Cancer Lett, 277, 821.
Head: Prof. Dr. Olaf Witt
Pediatric Oncology (G340)
69120 Heidelberg
Tel: +49 6221 42 3570
E-Mail: o.witt@dkfz.de
developmental pathways
dlerenuauon
HDAC8
HDAC5
HDAC9
apoptosis
HDAC8
HDAC1
HDAC1
HDAC8
prollferauon
HDAC2
HDACx
self renewal
reslsLance Lo chemoLherapy
HDACx
anchorage lndependenL growLh
pedlaLrlc cancer cell
HDAC family
members control
hallmarks of
pediatric neuronal
cancers.
Molecular Oncology of Solid Tumors
Metastasis and related translational research
represent a key interest of the Clinical Co-
operation Unit Molecular Oncology of Solid
Tumors. The group has contributed, e.g., to
the discovery of major regulatory mechanisms
driving expression of the urokinase receptor
(u-PAR), one of the most relevant metastasis-
related genes, and provided rst evidence for
tumor specicity of particular u-PAR transcrip-
tional regulators in resected gastrointestinal
cancers, delineating novel prognostic high-risk
groups and molecular staging models. Further-
more, the group demonstrated that the novel
tumor suppressor Pdcd4 inhibits metastasis by
regulating u-PAR, and that the loss of Pdcd4 is
an independent prognostic marker. As a major
mechanism downregulating Pdcd4, the group
described microRNA-21 which post-transcrip-
tionally downregulates Pdcd4 and stimu-
lates three different steps of the metastastic
cascade. Regarding translational research, we
found that the EGFR-antagonist Cetuximab at-
tenuates in vivo metastasis and u-PAR gene ex-
pression in non-small cell lung cancer (NSCLC),
and that u-PAR, with E-cadherin, is a novel
biomarker of Cetuximab sensitivity in NSCLC.
Taken together, the group has shown that it is
possible to individualize solid tumor staging
by mechanisms regulating metastasis, and to
dene novel high-risk groups and response
markers with them. Future activities will focus
on systematic projects on master pathways of
metastasis, microRNAs in metastasis, and their
implications for targeted therapy.
Future Outlook:
The group aims to:
pursue a systematic approach towards
tumor cell/stroma interaction, tumor
progression and metastasis. One project
will emphasize tumor cell-stroma-cell
crosstalk and processes such as epithe-
lial mesenchymal transition (EMT) with
microdissected tissue of gastrointestinal
cancer patients, analyzing these compart-
ments with gene expression, methylation
and microRNA proles. Results will be cor-
related with clinical prognosis and lead to
multiple functional spin-off projects on
specic networks of tumor-stroma-cell
interaction. A second project will compare
resected metastasis against primary tu-
mor and normal tissue using gene expres-
sion proling, microRNA proling, deep
sequencing and genome sequencing to
identify master pathways regulating me-
tastasis. Further tumor entities will be
added to investigate pathways which are
independent of the tumor type.
increase research on the specic role of
microRNAs in tumor progression and me-
tastasis
intensify translational studies parallel-
ing clinical studies on novel targeted
therapeutics and their interactions with
other therapeutics, to study their ability
to regulate metastasis, and to implicate
novel molecular markers of therapy re-
sponse and resistance, especially out of
the eld of metastasis-related molecules
and microRNAs.

ESSENTIAL PUBLICATIONS: (1.) Asangani I.A. et al.
(2009). MicroRNA-21 (miR-21) post-transcriptional-
ly downregulates tumor suppressor Pdcd4 and stim-
ulates invasion, intravasation and metastasis in colo-
rectal cancer. Oncogene, 27, 21282136. (2.) Nikolova D.
et al. (2009). Cetuximab attenuates metastasis and
u-PAR expression in non-small cell lung cancer: u-PAR
and E-cadherin are novel biomarkers of cetuximab
sensitivity. Cancer Res., 69, 24612470. (3.) Mudduluru
G. et al. (2011). Regulation of Axl receptor tyrosine ki-
nase expression by miR-34a and miR-199a/b in solid
cancer. Oncogene, 30, 28882899. d (4.) Rasheed SAK.
et al.(2010). First evidence that the antimalarial drug
artesunate inhibits invasion and in vivo metastasis in
lung cancer by targeting essential extracellular pro-
teases. Int. J. Cancer, 127, 14751485.
Head: Prof. Dr. Dr. Heike Allgayer
Molecular Oncology of Solid Tumors (G360)
69120 Heidelberg
Tel: +49 621 383 2226
E-Mail: h.allgayer@dkfz.de
and Dept. of Experimental Surgery, Medical
Faculty Mannheim, Ruprecht Karls University
Heidelberg
Chicken chorioallantoic membrane
(CAM) assay: Primary tumor in the
upper CAM.
Molecular Oncology of Gastrointestinal
Tumors (G180)
69120 Heidelberg
Tel: +49 6221 42 3140
E-Mail: r.offringa@dkfz.de
The Division Molecular Oncology of Gastro-
intestinal Cancers was founded in 2011 with
support from the KH Bauer Foundation. The
decision to direct research efforts to pancre-
atic cancer was based on the urgent unmet
medical need this disease represents, with in-
cidence and mortality rates still being almost
equal, and the fact that Heidelberg University
hosts the European Pancreas Center, one of
the worlds leading clinics for the treatment of
pancreatic cancer.
Our research aims at the implementation of
immunotherapy in conjunction with surgery,
chemotherapy and/or small molecule inhibi-
tors. The choice for immunotherapy was in-
spired by recent successes with this approach
in the clinic for other cancers, as well as emerg-
ing pre-clinical evidence that redirection of im-
mune pathways is one of the most promising
avenues towards more effective non-surgical
treatment of pancreatic cancer.
Our therapeutic strategy primarily involves
two approaches:
Stimulation of the endogenous immune
potential, in particular in the tumor stro-
ma, by means of agonist immunostimula-
tory monoclonal antibodies
Exploitation of the most powerful mode
of immunotherapy: infusion of ex vivo
engineered autologous T-lymphocytes
Patient-based research is supported by
the excellent availability of patient biop-
sies, including the tissue that represents
the interface between tumor and immune
system: tumor-draining lymph nodes. Our
research in mice focuses on genetically en-
gineered, autochthonous tumor models.
Future Outlook:
It is essential that our research does not stop
at the threshold between lab and clinic. This is
why we, together with our partners in the Uni-
versity Hospital and at the National Center for
Tumor Diseases (NCT) Heidelberg, are setting
up a pipeline for rationally designed clinical
trials in pancreatic cancer. Biomarker research
constitutes a pivotal aspect of this rational de-
sign, both with respect to patient stratication
and evaluation of therapy efcacy.
Initial studies will be staged in patients with
non-resectable pancreatic cancer, for which
median survival time is ~6 months. Since this
leaves insufcient time to boost endogenous
T-cell immunity, our approach focuses on
boosting endogenous innate immunity or, al-
ternatively, replenishing the patients immune
system with ex vivo engineered autologous
T-cells. Since the median survival time of pa-
tients diagnosed with resectable disease is ~1.5
years, modulation of endogenous T-cell immu-
nity will be considered in this patient group.
Although phase I safety studies generally in-
volve end stage patients, it is important that
further studies aimed at harnessing the en-
dogenous immune response are implemented
in the context of rst-line treatment, before
the patients immune system has deteriorat-
ed due to progressive disease and cytotoxic
anti-cancer regimens. In practical terms, this
currently means combination with standard of
care chemotherapy (gemcitabine) for non-re-
sectable disease, and (neo)adjuvant treatment
for resectable disease.
ESSENTIAL PUBLICATIONS: (1.) Oliveira C.C .et al.
(2010). The nonpolymorphic MHC Qa-1b mediates
CD8+ T cell surveillance of antigen-processing de-
fects. J Exp Med, 207, 207221. (2.) Offringa R. (2009).
Antigen choice in adoptive T-cell therapy of can-
cer. Curr Opin Immunol, 21, 190199. (3.) Bos R. et al.
(2008). Balancing between antitumor efcacy and
autoimmune pathology in T-cell-mediated targeting
of carcinoembryonic antigen. Cancer Res, 68, 8446
8455. (4.) van Hall T et al. (2006). Selective cytotoxic T-
lymphocyte targeting of tumor immune escape vari-
ants. Nat Med, 12, 417424.
Molecular Oncology of Gastrointestinal Tumors
Division
Head: Prof. Dr. Rienk Offringa
Tumorinltrating lymphocytes (TILs) are a good source
of tumor-reactive T-cells. Although their activity is
restrained by the tumor microenvironment, these T-cells
can be effectively re-activated and expanded in vitro, also
in the case of pancreatic ductal adenocarcinoma (see
microscopic image; I. Poschke & J. Hermes). This offers a
promising perspective for the development of adoptive
T-cell therapy for this disease (see inset).
Tumor fragment
T-cells
Neurooncology
The clinically oriented research focusses on
the development of diagnostic, prognostic and
predictive biomarkers in anaplastic glioma and
glioblastoma. This research is done in collabo-
ration with the Epigenetics group at the DKFZ,
funded by the Federal Ministry of Education
and Research (BMBF) and building on two larg-
er randomized trials, which have been coordi-
nated from the clinical neurooncology unit. A
second focus is on unravelling the molecular
mechanisms of several targeted therapies in
glioblastoma, like the protein kinase C beta
inhibitor, enzastaurin, the mammalian target
of rapamycin inhibitor, temsirolimus and the
soluble CD95, APG101 plus the understanding
of the interaction between these therapies
and radiation. In an ongoing effort, the group
is aiming at developing normal hematopoietic
stem cells into therapeutic vehicles. The chal-
lenges and interactions here are the molecular
mechanisms of specic lesions-tropisms as
well as the implementation of a safe, clinically
useful lentiviral transduction system. With a
specic focus on vascular endothelial growth
factor receptor 2 and regulator of G protein
signaling 4, the group seeks to understand the
fundamental principles of evasive resistance
against the classical anti-angiogenic agents
and, with modication, in radiation therapy.
Ultimately, the research in the Clinical Co-
operation Unit (CCU) Neurooncology should
focus on problems derived from the clinical
Neurooncology Program, with the clear aim to
translate the results back into the clinic.
Future Outlook:
Given a new biomarker, which optimally would
be sufcient to guide therapy decisions, this
will be characterized, developed and explored
for its potential in diseases other than brain
Head: Prof. Dr. Wolfgang Wick
Neurooncology (G370)
Department of Neurooncology Heidelberg
University Hospital and National Center for
Tumor Diseases Heidelberg
69120 Heidelberg
Tel: +49 6221 56 7075
Fax: +49 6221 56 7554
E-Mail:
wolfgang.wick@med.uni-heidelberg.de
tumors. Currently, one such predictive marker
for anaplastic glioma is under research. Using
a similar approach, a study cohort of elderly
patients with malignant glioma will be char-
acterized for differential methylation patterns
compared to the standard malignant glioma in
middle-aged patients aiding the understand-
ing of the comparatively worse prognosis.
From this and other research on targeted ther-
apies, new molecules and ultimately, points
for intervention are to be developed. Here, the
focus is on small molecule screens and com-
pound development. With the establishment
of a new group on multiphoton-microscopy
in the CCU, the core eld of angiogenesis and
brain metastases will be strengthened. The
focus of this group is to understand the mode
of action of anti-angiogenic therapies in the
brain and to elucidate the specic properties
of cancer cells that successfully establish brain
metastases. As with other projects, the group
is strongly linked to the CCU Neuropathology
and the experimental imaging departments
at both the Head Clinic and the DKFZ. This will
be of utmost importance for the transfer of re-
search results to the clinic.
ESSENTIAL PUBLICATIONS: (1.) Wick W. et al. (2009).
NOA-04 Randomized Phase III Trial of Sequential Ra-
diochemotherapy of Anaplastic Glioma With PCV or
Temozolomide. J. Clin. Oncol., 27, 58745880. (2.) Wick
W. et al. (2012). Temozolomide chemotherapy alone
versus radiotherapy alone for malignant astrocyto-
ma in the elderly: the NOA-08 randomised, phase
3 trial. Lancet Oncol. 13, 707715. (3.) Berger B. et al.
(2010) Defective p53 antiangiogenic signaling in glio-
blastoma. Neuro-Oncol, 12, 894907. (4.) Wick A. et al.
(2011) Bevacizumab does not increase the risk of re-
mote relapse in malignant glioma. Ann Neurol, 69,
586592.
Blood vessel
morphology and
function imaged by
in vivo MPLSM.
Neuropathology
The Clinical Cooperation Unit Neuropathology
was founded in 2007. Our research focuses on
molecular genetics of pediatric and adult tu-
mors of the central nervous system, the func-
tion of neurobromin, and the molecular refer-
ence analysis for brain tumor studies.
Prof. A. Korshunov examines pediatric brain
tumors in close cooperation with other groups
from the DKFZ, with a focus on medulloblas-
tomas, pilocytic astrocytomas and ependymo-
mas. We are participating in the International
Cancer Genome Consortium (ICGC). For adult
gliomas our main interest is in diffuse astro-
and oligodendroglial tumors characterized by
IDH1 mutations. Dr. D. Capper and F. Sahm are
characterizing this and other mutations and
are developing diagnostic tools for routine ap-
plications. Dr. S. Pusch and Dr. J. Balss are con-
ducting research on the function of mutated
IDH1. The tumor syndrome neurobromatosis
type 1 is caused by mutations of the NF1 gene
which encodes neurobromin. Many biological
features of neurobromin are mediated by its
RasGAP activity. However, additional functions
have been suggested. A group headed by Dr.
D. Reuss is uncovering alternative pathways of
neurobromin to inhibit tumor cell growth.
Our molecular diagnostic program is headed
by Prof. C. Hartmann and serves multiple clini-
cal studies by providing data such as muta-
tional status of tumor suppressor genes or on-
cogenes. Our clinical partners compare these
data with clinical parameters.
Head: Prof. Dr. Andreas von Deimling
Neuropathology (G380)
69120 Heidelberg
Tel: +49 6221 56 4650
E-Mail: andreas.vondeimling@dkfz.de
Future Outlook:
We will contribute to genomic analyses of
medulloblastoma and pilocytic astrocytoma
within the ICGC: Acquisition of high-quality tu-
mor and matched germline samples according
to ICGC guidelines; histopathological assess-
ment; acquisition of clinical data and follow-up
information and molecular characterization of
samples using previously proposed diagnostic
and prognostic markers. In cooperation with
DKFZ partners, we have designed a conditional
knock-in mouse model for the IDH1-R132H mu-
tation. We will attempt to create mutant IDH1
driven mouse brain tumor models. This likely
will require combination with other tumori-
genic alterations such as TP53 mutations and
tissue specic expression at different times of
development.
Future tasks within the NF1 project are to ver-
ify our results from cellular models in animal
models and to extend our understanding of
potential alternative NF1 pathways. We will use
well characterized NF1 mouse models in which
mice develop multiple neurobromas closely
resembling human disease. In our molecular
diagnostic program we attempt to meet the
growing demand from our clinical partners
within the DKFZ as well as from multicenter
studies. We are prepared to adapt our molecu-
lar diagnostic assays to the needs of individual
study protocols.
ESSENTIAL PUBLICATIONS: (1.) Balss J. et al. (2008).
Analysis of the IDH1 codon 132 mutation in brain tu-
mors. Acta Neuropathol., 116, 597602. (2.) Capper D.
et al. (2009). Monoclonal Antibody Specic for IDH1
R132H Mutation. Acta Neuropathol., 118, 599601. (3.)
Korshunov A. (2010). Molecular staging of intracra-
nial ependymoma in children and adults. J. Clin. On-
col., 28, 31823190. (4.) Hartmann C. et al. (2010). Pa-
tients with IDH1 wild type anaplastic astrocytomas
exhibit worse prognosis than IDH1 mutated glioblas-
tomas and IDH1 mutation status accounts for the un-
favorable prognostic effect of higher age: implica-
tions for classication of gliomas. Acta Neuropathol.,
120, 707718.
Example for development of a diagnostic tool. Our
antibody H09 specically binds to IDH1 protein
with the R132H mutation. All tumor cells impose in
a strong brown color while normal brain tissue is
stained blue and grey.
Experimental Neuroimmunology
A paradigmatic autoimmune disease of the
central nervous system (CNS) is multiple scle-
rosis. On the other hand a hallmark of intrinsic
CNS tumors is profound systemic and local im-
munosuppression. The cellular and molecular
mechanisms that are involved in the deregula-
tion of CNS immunity in theses diseases are
incompletely understood but probably involve
pathways common to both, too much immune
response in multiple sclerosis and too little
immune response in brain tumors. Our group
is interested in the metabolic control of CNS
immunity and brain tumor development. The
long-term goal is to identify crucial metabolic
switches that may serve as therapeutic targets.
In the past years we have identied key steps
in the catabolism of the essential amino acid
tryptophan as an endogenous mechanism,
that restricts unwanted immune responses.
These discoveries have led to the identication
of novel therapeutic approaches and diagnos-
tic tools that are currently undergoing clinical
evaluation. Recently we have identied a key
receptor of tryptophan catabolites that not
only mediates tumor-promoting host cell in-
teractions, but also tumor cell intrinsic mecha-
nisms to sustain tumor growth and invasive-
ness. These recent discoveries open a new view
of the role of tryptophan catabolism in cancer
and identify novel therapeutic targets.
Future Outlook:
The discovery that TDO-derived tryptophan
catabolites (kynurenines) drives brain and
probably other types of cancer via the aryl hy-
drocarbon receptor (AHR) raises further ques-
tions which will be tackled in the future. This is
especially important as tryptophan catabolism
has evolved in recent years as a key metabolic
pathway in cancer biology and immune regu-
lation and early clinical trials in cancer patients
start to employ pharmacological inhibitors. Fu-
ture basic science projects will address (a) the
regulation of tryptophan catabolism in can-
cer cells at the transcriptional and posttran-
scriptional level by host signals, (b) the role of
tryptophan catabolism in stem cell maintain-
ance, (c) the role of tryptophan catabolism in
angiogenesis and (d) the role of tryptophan ca-
tabolism in autoimmune neuroinammation.
Future translational projects will deal with (e)
the development of mesenchymal stem cell
therapy for clinical application in patients with
multiple sclerosis and with (f) the identi-
cation of drugs interfering with the AHR as
potential therapeutics for malignant glioma,
targeting both cell autonomous processes and
tumor-associated immunosuppression. Finally,
we aim at implementing the rst specic im-
munotherapy for patients with IDH1-mutated
low-grade and anaplastic glioma.
ESSENTIAL PUBLICATIONS: (1.) Platten M. et al. (2005).
Treatment of autoimmune neuroinammation with
a synthetic tryptophan metabolite. Science, 310, 850
855. (2.) Opitz C.A.. et al. (2009). Toll-like receptor en-
gagement enhances the immunosuppressive prop-
erties of human bone marrow-derived mesenchymal
stem cells by inducing indoleamine-2,3-dioxyge-
nase-1 via interferon- and protein kinase R. Stem
Cell, 27, 909919. (3.) Platten M. et al. (2009). Blocking
angiotensin converting enzyme induces potent regu-
latory T cells and modulates TH1- and TH17-mediated
autoimmunity. Proc Natl Acad Sci, 106, 1494814953.
(4.) Opitz C.A. et al. (2011). An endogenous tumour-
promoting ligand of the human aryl hydrocarbon re-
ceptor. Nature, 478, 197203.
Head: Prof. Dr. Michael Platten
Experimental Neuroimmunology (G160)
Department of Neurooncology
D-69120 Heidelberg
Tel: +49 6221 56 7107
Fax: +49 6221 56 5935
E-Mail: m.platten@dkfz.de
Brain MRI scan of mice
with brain tumors that
catabolize tryptophan
(+ TDO) compared with
tumors that do not
catabolize tryptophan
(- TDO) and do not
form large tumors.
Activation of the
immunosuppressive
AHR-program (TiPARP)
in an immune cell
(LCA) inltrating
a tryptophan
catabolizing tumor.
Experimental Therapies for Hematologic
Malignancies
Max-Eder-Junior Research Group
Despite recent advances, most cancers of the
blood and bone marrow remain incurable.
Our group is therefore focused on understand-
ing critical pathophysiological mechanisms of
hematologic malignancies to enable the iden-
tication of innovative therapeutic targets and
treatment strategies. Together with the Clini-
cal Cooperation Unit Molecular Hematology/
Oncology (G330, Prof. A. Krmer), we are cur-
rently investigating the clustering of supernu-
merary centrosomes. This is a well-recognized
cellular process on which cancer cell growth is
dependent. We are therefore working to deci-
pher the mechanism of centrosomal clustering
in hematologic malignancies with a view to
the development of specic inhibitors to ex-
ploit this mechanism for therapeutic ends.
In our model disease, multiple myeloma, we
aim to discover molecular mechanisms of
the pivotal transition from its premalignant
precursor state to the active malignant stage.
Here, we are focusing on the regulation of the
cell cycle that seems to prevent clonal growth
of premalignant stages compared to active
myeloma. We are also interested in the evalu-
ation of novel agents, which inhibit cellular
pathways known to be important in myeloma
pathogenesis. This work is done in collabora-
tion with our industry partners who provide
promising compounds for assessment in our
extensive pre-clinical models. We also partici-
pate in several national and international clini-
cal trials including rst-in-man applications as
well as rst-in-class studies.
Future Outlook:
All our projects are aimed at the discovery of
new therapeutic targets, investigating new
treatment strategies, and ultimately, improving
patient outcome. Our group has 3 major goals:
Develop novel therapeutic approaches
based on centrosomal clustering: We aim
Head: Dr. Marc S. Raab
Experimental Therapies for Hematologic
Malignancies (G170)
69120 Heidelberg
Tel: +49 6221 42 1450
E-Mail: m.raab@dkfz.de
to further develop our rst lead com-
pound towards clinical application and to
screen for novel inhibitors of centrosomal
clustering.
Discover key events in myeloma patho-
genesis: We will investigate the piv-
otal transition from the pre-malignant,
asymptomatic to malignant, symptomat-
ic stages of plasma cell dyscrasias in order
to understand the pathophysiology and
thereby identify novel targets.
Translate small molecule therapeutics
from bench to clinical trials: This includes
the evaluation of novel agents in the pre-
clinical setting and the initiation of early
phase clinical trials in hematologic ma-
lignancies, with a focus on personalized
therapy for multiple myeloma.
ESSENTIAL PUBLICATIONS: (1.) Raab M.S. et al. (2012).
GF-15, a novel inhibitor of centrosomal clustering,
suppresses tumor cell growth in vitro and in vivo.
Cancer Research, 72, 53745385. (2.) Raab M.S. et al.
(2009). Multiple Myeloma. Lancet, 374, 324339. (3.)
Raab M.S. et al. (2009). Targeting PKC: A novel role
for beta-catenin in ER stress and apoptotic signaling.
Blood. 113, 15131521. (4.) Raab M.S. et al. (2007). Target-
ed treatments to improve stem cell outcome: old and
new drugs. Bone Marrow Transplant, 40, 11291137.
Multipolar mitosis of a mouse
xenograft under treatment
with a prototype inhibitor of
centrosomal clustering.
Head: Dr. Bjrn Tews
Molecular Mechanisms of Tumor Cell Invasion
Molecular Mechanisms of Tumor Cell Invasion
(V077)
69120 Heidelberg
Tel: +49 (0)6221 42 1570
E-Mail: b.tews@dkfz.de
Glioblastoma is the most aggressive brain tu-
mor with a poor prognosis, reected by a me-
dian patient survival of about 14 months. The
invasive nature of glioma cells mainly accounts
for their resistance to current treatment mo-
dalities, as the diffusely inltrating tumor cells,
which evade surgical resection and survive
treatment, inevitably give rise to recurring
tumors. Substantial evidence has been accu-
mulated to suggest that lysophospholipids are
involved in tumorigenesis; they are especially
important for therapeutic resistance of tumors
by regulating tumor cell migration. We inves-
tigate lysophospholipid signaling depend-
ing on the extracellular matrix environment
and determine the consequences of different
regimens of in vitro and in vivo chemotherapy.
Analyzing lipid proles of different glioma
cell populations and signaling of related G-
protein coupled receptors is a main part of our
research. The ultimate goal is to identify the
functional consequences of these deregulated
signaling cascades on tumor cell migration
and invasion. Our methodological repertoire
includes modulation of GPCR expression and
signaling, different in vitro paradigms to study
cell migration and invasion, such as organotyp-
ic slice cultures, Real-time Cell Analyses (RTCA),
time-lapse microscopy and in vivo xenograft-
ing techniques combined with imaging of tu-
mor cells in different transgenic mouse lines.
Future Outlook:
Understanding the complex lysophospholipid
signaling cascades upon different treatments
will provide important information to design
new, tailored therapies for patients suffer-
ing from glioma by combining established
chemotherapeutics with the application of
sphingolipid-modulating antibodies and small
molecules.
ESSENTIAL PUBLICATIONS: (1.) Dittmann L.M. et al.
(2011). Downregulation of PRDX1 by promoter hyper-
methylation is frequent in 1p/19q-deleted oligoden-
droglial tumours and increases radio- and chemosen-
sitivity of Hs683 glioma cells in vitro. Oncogene. 31,
34093418. (2.) Barbus S. et al. (2011). Differential reti-
noic acid signaling in tumors of long- and short-term
glioblastoma survivors. J Natl Cancer Inst. , 103, 598
606. (3.) Tews B. et al. (2007). Hypermethylation and
transcriptional downregulation of the CITED4 gene
at 1p34.2 in oligodendroglial tumours with allelic
losses on 1p and 19q. Oncogene., 26, 50105016. (4.)
Tews B. et al. (2006). Identication of novel oligoden-
droglioma-associated candidate tumor suppressor
genes in 1p36 and 19q13 using microarray-based ex-
pression proling. Int J Cancer., 119, 792800.
Foundation (CHS).
Real-time Cell Analysis (RTCA) of cells
overexpressing a wildtype (wt) or inactive (mut)
form of a sphingolipid G-protein coupled receptor
which negatively regulates cell adhesion and
spreading on a CNS myelin substrate. Cell Index (CI)
decribes a relative change in electrical impedance
representing the morphological cell status. Data
shown are mean values SEM.
Neuropeptides
Head: Dr. Valery Grinevich
Neuropeptides (V078)
69120 Heidelberg
Tel: +49 6221 486 174
E-Mail:
Valery.Grinevich@mpimf-heidelberg.mpg.de
Foundation (CHS).
Our new laboratory will focus on the dis-
section of the mechanisms of neuropeptide
action in the brain, from molecular via ana-
tomical to the whole organism level. We will
thus employ genetic, molecular, anatomical,
viral, optogenetic and behavioral approach-
es to study the effects of addressed axonal
release of various neuropeptides within the
distinct brain regions controlling stress and
fear responses, maternal and social behaviour.
Furthermore, our group will use animal models
of psychiatric diseases, including anxiety dis-
orders and autism, to study the possible contri-
bution of neuropeptides to the pathogenesis
of the respective human diseases.
ESSENTIAL PUBLICATIONS: (1.) Knobloch S. et al. (2012).
Evoked axonal oxytocin release in the central amyg-
dala attenuates fear response. Neuron, 73, 553566.
(2.) Liu Y. et al. (2010). Involvement of transducer of
regulated cAMP response element-binding protein
activity CREB activity on corticotropin releasing hor-
mone transcription. Endocrinology, 151, 109118. (3.)
Grinevich V. et al. (2009). TgArc/Arg3.1-d4EGFP in-
dicator mice: a versatile tool to study brain activi-
ty changes in vitro and in vivo. J. Neurosci. Meth. 184,
2536. (4.) Grinevich V. et al. (2005). Monosynaptic
pathway from rat vibrissa motor cortex to facial mo-
tor neurons revealed by lentivirus-based axonal trac-
ing. J. Neurosci., 25, 82508258.
The image depicts virus-mediated cell-type specic
uorescent labeling of hypothalamic oxytocin
neurons, as revealed by immunohistochemistry
(green: Venus, red and blue: oxytocin and
vasopressin-immunoreactivity, respectively),
and represents the targets for oxytocin axons
originating from the hypothalamic paraventricular
nucleus in the rat forebrain. Image illustrated by
Julia Kuhl.
Join us!
142
A
Abdollahi, Dr. Dr. Amir 106
Allgayer, Prof. Dr. Dr. Heike 131
Angel, Prof. Dr. Peter 34
Arnold, Prof. Dr. Bernd 88
Augustin, Prof. Dr. Hellmut 40
B
Beckhove, Prof. Dr. Philipp 86
Boulant, Dr. Steeve 117
Boutros, Prof. Dr. Michael 68
Brady, Dr. Nathan 73
Brenner, Prof. Dr. Hermann 82
Bukau, Prof. Dr. Bernd 43
Burwinkel, Prof. Dr. Barbara 83
C
Cerwenka, PD Dr. Adelheid 91
D
Debus, Prof. Dr. Dr. Jrgen 100
Delecluse, Prof. Dr. Dr. Henri-Jacques 114
de Villiers, Prof. Dr. Ethel-Michele 113
Dick, PD Dr. Tobias P. 38
Diederichs, Dr. Sven 71
E
Edgar, Prof. Dr. Bruce 41
Eils, Prof. Dr. Roland 66
Eisenhut, Prof. Dr. Michael 98
Essers, Dr. Marieke 53
F
Feuerer, Dr. Markus 92
Fischer, Dr. Andreas 52
Franke, Prof. Dr. Werner W. 46
G
Garca-Sez, Dr. Ana 72
Gissmann, Prof. Dr. Lutz 111
Grinevich, Dr. Valery 139
Grummt, Prof. Dr. Ingrid 45
H
Haberkorn, Prof. Dr. Uwe 102
Hamacher-Brady, Dr. Anne 75
Hansman, Dr. Grant 116
Hell, Prof. Dr. Stefan 104
Hemminki, Prof. Dr. Kari 80
Herzig, Prof. Dr. Stephan 39
Hfer, Prof. Dr. Thomas 67
Hofmann, Dr. Thomas G. 50
Hoheisel, Dr. Jrg D. 65
Huber, Prof Dr. Dr. Peter 101
J
Jahn, Dr. Thomas 74
K
Kaaks, Prof. Dr. Rudolf 79
Klingmller, PD Dr. Ursula 37
Kopp-Schneider, Prof. Dr. Annette 81
Krmer, Prof. Dr. Alwin 128
Index Krammer, Prof. Dr. Peter 87
Kyewski, Prof. Dr. Bruno 89
L
Langowski, Prof. Dr. Jrg 61
Lichter, Prof. Dr. Peter 63
Liu, Dr. Hai-Kun 51
Lyko, Prof. Dr. Frank 36
M
Maier-Hein, Dr.-Ing. Lena 107
Martin-Villalba, Prof. Dr. Ana 44
Meinzer, Prof. Dr. Hans-Peter 103
Milsom, Dr. Michael 54
Monyer, Prof. Dr. Hannah 42
N
Nettelbeck, PD Dr. Dirk M. 115
Niehrs, Prof. Dr. Christof 33
O
Offringa, Prof. Dr. Rienk 132
Oskarsson, Dr. Thordur 56
P
Pereira, Dr. Gislene 48
Pster, Prof. Dr. Stefan 64
Plass, Prof. Dr. Christoph 78
Platten, Prof. Dr. Michael 136
R
Raab, Dr. Marc S. 137
Riemer, PD Dr. Dr. Angelika 118
Rodewald, Prof. Dr. Hans-Reimer 90
Rommelaere, Prof. Dr. Jean 110
Rsli, Dr. Christoph 55
Rsl, Prof. Dr. Frank 112
Roth, Prof. Dr. Wilfried 126
S
Schlegel, Prof. Dr. Wolfgang 99
Schlemmer, Prof. Dr. Heinz-Peter 96
Schtz, Prof. Dr. Gnther 47
Schwab, Prof. Dr. Manfred 60
Semmler, Prof. Dr. Dr. Wolfhard 97
Stcklin, Dr. Georg 49
T
Teleman, Dr. Aurelio 70
Tews, Dr. Bjrn 138
Trumpp, Prof. Dr. Andreas 32
U
Ulrich, Prof. Dr. Cornelia 124
Utikal, Prof. Dr. Jochen 127
V
von Deimling, Prof. Dr. Andreas 135
von Engelhardt, Dr. Jakob 57
von Kalle, Prof. Dr. Christof 122
von Knebel Doeberitz, Prof. Dr. Magnus 123
W
Wick, Prof. Dr. Wolfgang 134
Wiemann, PD Dr. Stefan 62
Witt, Prof. Dr. Olaf 130
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