The Apc tumour suppressor gene is mutated in 80% of colorectal cancers. Mechanistically its major function as a tumour suppressor is to negatively regulate Wnt signalling, preventing the activation of Wnt target genes. Due to the difficulties of studying intestinal cells ex vivo, a plethora of studies have been performed investigating gene function within the murine intestine following Apc loss. In this grant we propose to validate the Drosophila fly intestine as a model system to investigate Apc loss. Specifically we aim to use the Drosophila intestine as a screen for Wnt targets that are functionally important for the phenotypes of Apc loss. These experiments could dramatically reduce the numbers of murine intestinal experiments performed and yield new insights in to colorectal carcinogenesis.
- Research Review 2013: Oncology research with the fruit fly
Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF (2014). Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut 63(3): 480-93 doi: 10.1136/gutjnl-2012-303883
Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, Schwitalla S, Kalna G, Ogg EL, Athineos D, Timpson P, Vidal M, Murray GI, Greten FR, Anderson KI, Sansom OJ (2013). ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 12(6): 761-73 doi: 10.1016/j.stem.2013.04.006
Cordero JB, Sansom OJ (2012) Wnt signalling and its role in stem cell-driven intestinal regeneration and hyperplasia. Acta Physiologica 204(1): 137-43 doi:10.1111/j.1748-1716.2011.02288.x
Cordero JB, Stefanatos RK, Scopelliti A, Vidal M, Sansom OJ (2012) Inducible progenitor-derived Wingless regulates adult midgut regeneration in Drosophila. The EMBO Journal 31 (19): 3901-3917 doi:10.1038/emboj.2012.248