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Helen Abud

Dr Helen Abuds current research programs

Dr Helen Abuds current research programs


Snail1, Wnt Signaling, Stem Cell Development and Cancer Wnt Signaling regulates Snai1 expression and Cellular Localisation in the Mouse Intestinal Epithelial Stem Cell Niche Article

DNp73 and Stem Cells in Cancer Functional studies of the role of DNp73 and stem cells in Cancer Presentation at Conference Monash Comprehensive Cancer Consortium

Cancer and development

Snai1 and Wnt Signalling


Wnt signaling normally stimulate growth by increasing Level of catenin Required for maintenance of epithelium Wnt signaling does different things: - Promotes cell proliferation, - self-renewal, facilitates migration Too much Wnt signaling SELF SUFFICIENCY IN GROWTH SIGNALS Promote CANCER/TUMOUR formation

Dr Abuds work: to find out relationship between Snai1 and Wnt Signalling in the intestines

Snai1 and Wnt Signaling


Snai1 transcription factor, member of Snail family Snai1 high level of expression throughout stem cell population Evidence LGR5 marker (stem cells) and Snai1 stain Snail1 is known to be the factor that keeps cells in the stem-cell state Maintaining stemness which induces high level of cell proliferation

Snai1 stain Wnt signaling found here!

LGR5 stain

A crypt base columnar cell (CBC cell)

Snai1 and Wnt signaling


How it leads to a disease state?
Wnt signaling can be a key factor to tumour formation If it occurs without regulation Mutation of APC (Tumour supressor) which is found in most tumour polyps INCREASE SNAI1 EXPRESSION Evidence: immunohistochemical stain Model on Apcmin mice more Snai1 expression develop polyps

Apcmin polyp tissue

Normal colon tissue

Snai1 and Wnt signaling


The story so far
Cancer is an acquired development (benign malignant) More Wnt signaling, more Snai1 expression, more cell proliferation Uncontrolled cell proliferation leads to cancer

Therefore:
Snai1 is the master regulator of stem cell populations

Snai1 and Wnt Signaling


Concept of EMT happens in both NORMAL DEVELOPMENT and TUMOUR GENESIS Epithelial cells are very polarised in NORMAL DEVELOPMENT but in TUMOUR GENESIS they start to lose their

polarity and become

more This is when EPITHELIAL cells become more MESENCHYMAL (EMT) After EMT, they can become enterocytes for example.

migratory

Snai1 is involved in EMT (as a regulator) It induces metastasis and maintaining stemness.

Snai1 and Wnt Signaling


Relationship between normal tissue development and cancer Development

THE SWITCH IS ALWAYS TURNED ON!


Even when Wnt signaling is turned off, Snai1 is still present. Suggest: There are many other mechanisms that regulate Snai1 and control stem cell population (ongoing research). Knock out of any Protein participants in these pathways can cause dramatic phenotype LOSS OF INTESTINAL STEM CELLS

The threshold of Wnt signals has to be just right!!

Snai1 and Wnt Signaling


The story continues

Threshold for Wnt: During head-tail embryonic formation, there needs to be a gradient
in level of Wnt expression - Different ways a tissue can respond to Wnt signal; combination of Wnt receptor and inhibitory signals Dickkopf, RNF molecules (inhibit Wnt signals) Rspondins (enhance Wnt signals) - Different processes of development require different thresholds (in different organs) - ANTERIOR POSTERIOR embryonic patterning: head low Wnt and tail high Wnt

DNp73 mystery uncovered


P73 is a Tumour Suppressor protein similar p53 in both structure and function P53 guardian of the genome regulates cell cycles conserves stability of other proteins and reduce the chances of them undergo mutation Mutation of p53 has extremely high chances of leading to tumour formation. This can be Discovered in screening of tumourous tissue, DEFINITE MUTATION OF P53 Same screening done on tumourous tissue, hardly any mutations of p73 are found. WHY??

DNp73 mystery uncovered


DNp73 dominant negative p73
A spliced, short, truncated version of p73 Dominant negative inhibits actions of other proteins DNp73 binds to the full-length versions of p53 and p73 and inhibit their activities - Cell cycles are not regulated any of the 6 attributes of cancer cells can be acquired by cells DNp73 can be an oncoprotein upregulation is shown to cause intestinal polyp formation on mice