Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features
Dustin J. Flanagan, Raheleh Amirkhah, David F. Vincent, Nuray Gündüz, Pauline Gentaz, Patrizia Cammareri, Aoife J. McCooey, Amy M.B. McCorry, Natalie C. Fisher, Hayley L. Belnoue-Davis, Rachel A. Ridgway, Jeroen Lohuis, Joshua D.G. Leach, René Jackstadt, Kathryn Gilroy, Elisa Mariella, Colin Nixon, William Clark, Ann Hedley, Elke Markert, Douglas Strathdee, Laurent Bartholin, Keara L. Redmond, Emma Kerr, Daniel B. Longley, Fiona Ginty, Sanghee Cho, Helen G. Coleman, Maurice B. Loughrey, Alberto Bardelli, Tim Maughan, Andrew D. Campbell, Mark Lawler, Simon J. Leedham, Simon T. Barry, Gareth J. Inman, Jacco van Rheenen, Philip D. Dunne, Owen J. Sansom
Abstract
The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits.