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Wnt Signalling in Colorectal Carcinogenesis and Intestinal Homeostasis

Final Report Summary - WNT IN THE INTESTINE (Wnt signalling in colorectal carcinogenesis and intestinal homeostasis)

1. Using flies and mice to model intestinal homeostasis and transformation

We have developed a Drosophila model of CRC, which is providing great insight into the mechanisms involved in the disease. Furthermore, our results highlight that intestinal regeneration and transformation share many commonalities.

Using RNA interference and loss of function alleles we knocked down Apc1 from the adult Drosophila intestine. Our results indicate that Apc1 is not redundant to Apc2 in the Drosophila midgut, and that its depletion is sufficient to trigger ISC proliferation and hyperplasia in the midgut epithelium. This phenotype highly resembles that of the mammalian intestine, indicating a significant degree of evolutionary conservation in the biology of this tissue (Cordero et al., 2009). Therefore, this should act as an excellent system to identify key downstream signalling events following Apc1 loss.

We have performed microarray analysis from Apc1 deficient Drosophila midguts. We have identified many genes and pathways that are mis-regulated upon Apc1 loss. We have demonstrated that Jak/Stat signalling and Myc are activated and required for ISC proliferation following Apc1 loss. Furthermore, we show that parallel activation of Wnt/Myc and Jak/Stat signalling is essential for ISC proliferation during tissue regeneration and that Wg secreted from the intestinal epithelium is required for this process. Our results uncover an intimate connection between Wnt/Myc and Jak/Stat signalling, which mediates ISC proliferation during tissue regeneration as well as in transformation (Cordero et al., 2011; under review).

Using flies and mice we have demonstrated that Src hyperactivation is sufficient to drive ISC hyperproliferation and intestinal hyperplasia. Furthermore, activation of Src is required for intestinal regeneration in response to damage and hyperplasia following Apc loss.

We expect our work will lead to a better understanding of the cellular and molecular pathways involved in intestinal homeostasis, regeneration and transformation. Therefore our results hold great potential for the development of targeted colorectal cancer (CRC) therapies as well as for regenerative medicine.

2. Role of the immune system in tumor progression and invasion

Using a genetically defined Drosophila tumor model, we showed that TNF acts as a tumour promoter in the context of RasV12; scrib-/- tumors. Furthermore, TNF was expressed by tumour-associated haemocytes and such expression was necessary and sufficient for pathway activation in tumour cells. Our results provide novel mechanistic insights explaining the contrasting roles of the immune system in tumourigenesis and suggesting a strong dependency on the genetic composition of the tumour (Cordero et al., 2010). We aim to translate these results to our fly and mouse models of colorectal cancer.

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