View Program - 63rd Annual Drosophila Research Conference

Genetic mutations are the major driver of cancer development. Aberrations within the EGFR-Ras-MAPK signalling pathway are the most frequently observed in human cancer, making this pathway a good target for therapy. Another signalling pathway that is gaining increasing interest is the Hippo signalling pathway, due to its involvement in cancer. The Drosophila imaginal discs have been extensively used as a model to study patterns of cancer growth, as most cancers arise from the epithelial tissue. Using Drosophila imaginal discs, we have discovered that the output of the Ras signalling pathway in promoting proliferation versus differentiation is under the tight control of the Hippo pathway. This study identified a cluster of 26 genes that are only upregulated with simultaneous dysregulation of the EGFR and Hippo signalling pathways and are largely unaffected with a mutation in a single pathway. Here we used a Gal4/UAS system to drive Ras or Raf gain of function combined with Yki upregulation using an apterous driver to generate our cancer model. This leads to a dramatic overgrown phenotype of the wing imaginal disc compared to wild type discs and extends the larval developmental stage up to 9 days. We have used this model to perform an RNAi screening of the aforementioned 26 genes and have identified that downregulation of negative regulators of the EGFR signalling pathway led to a rescue of the observed overgrown phenotype. Between these screening hits, we are focusing our investigation on the gene sprouty. This is a negative regulator of the EGFR signalling pathway whose function as either a tumour suppressor or oncogene in cancer has shown conflicting findings. Upregulation of sprouty 2 (the human ortholog of Drosophila sprouty) is common in colorectal cancer where dysregulation of both the Hippo and EGFR pathways are reported. Several studies have shown that downregulation of sprouty 2 using siRNA led to decreased cancer proliferation and invasion. The similarity to our in vivo system has led us to investigate this gene further. Coupling an in vivo (Drosophila melanogaster) and in vitro model (colorectal cancer cell lines), we are investigating whether Sprouty can be a better target for therapy in those cancers where dysregulation of this gene could lead to a worse outcome.

Targeting the Ras/Raf/ERK negative regulator sprouty as a novel strategy for cancer therapy

**Targeting the Ras/Raf/ERK negative regulator sprouty as a novel strategy for cancer therapy**