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 G. Vázquez, David F. Vincent, William J. Faller, Michael C. Hodder, Alexander Raven, Sigrid Fey, Arafath K. Najumudeen, Douglas Strathdee, Colin Nixon, Mark Hughes, William Clark, Robin Shaw, Sander R. Hooff, David J. Huels, Jan Paul Medema, Simon T. Barry, Margaret C. Frame, Asier Unciti-Broceta, Simon J. Leedham, Gareth J. Inman, Rene Jackstadt, Barry J. Thompson, Andrew D. Campbell, Sabine Tejpar and Owen J. Sansom ()
Additional contact information
Joshua D. G. Leach: Cancer Research UK Beatson Institute
Nikola Vlahov: Cancer Research UK Beatson Institute
Petros Tsantoulis: University of Geneva
Rachel A. Ridgway: Cancer Research UK Beatson Institute
Dustin J. Flanagan: Cancer Research UK Beatson Institute
Kathryn Gilroy: Cancer Research UK Beatson Institute
Nathalie Sphyris: Cancer Research UK Beatson Institute
Ester G. Vázquez: University of Oxford
David F. Vincent: Cancer Research UK Beatson Institute
William J. Faller: Netherlands Cancer Institute
Michael C. Hodder: Cancer Research UK Beatson Institute
Alexander Raven: Cancer Research UK Beatson Institute
Sigrid Fey: Cancer Research UK Beatson Institute
Arafath K. Najumudeen: Cancer Research UK Beatson Institute
Douglas Strathdee: Cancer Research UK Beatson Institute
Colin Nixon: Cancer Research UK Beatson Institute
Mark Hughes: Cancer Research UK Beatson Institute
William Clark: Cancer Research UK Beatson Institute
Robin Shaw: Cancer Research UK Beatson Institute
Sander R. Hooff: Academic Medical Center
David J. Huels: Academic Medical Center
Jan Paul Medema: Academic Medical Center
Simon T. Barry: AstraZeneca
Margaret C. Frame: University of Edinburgh
Asier Unciti-Broceta: University of Edinburgh
Simon J. Leedham: University of Oxford
Gareth J. Inman: Cancer Research UK Beatson Institute
Rene Jackstadt: Cancer Research UK Beatson Institute
Barry J. Thompson: The Australian National University
Andrew D. Campbell: Cancer Research UK Beatson Institute
Sabine Tejpar: University of Leuven
Owen J. Sansom: Cancer Research UK Beatson Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

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.

Date: 2021
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DOI: 10.1038/s41467-021-23717-5

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