The intestinal epithelium is a highly self-renewing tissue, which is replenished by multipotent stem cells. Deregulation of normal intestinal homeostasis often results in malignant transformation. Colorectal carcinoma is one of the most common cancers in western world. Inactivating mutations of the Apc (Adenomatous Polyposis Coli) gene is key for colorectal cancer; up to 80% of sporadic colorectal cancers have Apc mutations.
The main tumour suppressive function of Apc is to negatively regulate Wnt signalling, however the functional significance of the pathways downstream of Apc remains elusive. Furthermore, the contribution of intestinal stem cells to colorectal cancer is unclear. The host laboratory has generated a mouse model to study the acute consequences of Apc loss in vivo. Using microarray analysis the lab has identified numerous novel Wnt target genes that are up regulated at all stages of colorectal carcinogenesis. These genes may be important modifiers of the Apc phenotypes but, given their number and potential redundancies, they cannot be tested in a high throughput manner in the mouse.
Drosophila melanogaster is one of the best model organisms to perform genetic screens. Recent reports have shown that the Drosophila adult gut has remarkable resemblance to the vertebrate intestine. Importantly, Drosophila intestinal stem cells have been unambiguously identified. In this proposal I will: A) Generate a Drosophila model of Apc driven gut tumourigenesis. B) Test the fly orthologues of the mouse candidate target genes in this system. C) Test the modifiers of the Drosophila phenotype in the mouse model of Apc loss. Ours is a novel approach, which takes advantage of two in vivo genetic model systems to shed light into the molecular and cellular mechanisms regulating malignant transformation within the intestinal epithelium.