Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis
Joshua D.G. Leach, Nikola Vlahov, Petros Tsantoulis, Rachel A. Ridgway, Dustin J. Flanagan, Kathryn Gilroy, Nathalie Sphyris, Ester Gil Vázquez, David F. Vincent, William J. Faller, Michael C. Hodder, Alexander Raven, Sigrid K. Fey, Arafath K. Najumudeen, Douglas Strathdee, Colin Nixon, Mark Hughes, William Clark, Robin Shaw, Tim Maughan, Manuel Salto‐Tellez, Philip Quirke, Viktor H. Koelzer, Philip D. Dunne, Andrew D. Beggs, Peter J. Campbell, Francesca M. Buffa, Chris Holmes, Rick Kaplan, Louise Brown, Mark Lawler, Joshua Hordern, Ian Tomlinson, Simon J. Leedham, Dion Morton, Sander R. van Hooff, David J. Huels, Jan Paul Medema, Simon T. Barry, Margaret C. Frame, Asier Unciti‐Broceta, Simon J. Leedham, Gareth J. Inman, René Jackstadt, Barry J. Thompson, Andrew D. Campbell, Sabine Tejpar, Owen J. Sansom
Abstract
Abstract Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype ( Ly6a/Sca1 + ) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF -mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.