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.
Bibliographical noteFunding Information:
S.T.B. is an employee of AstraZeneca. O.J.S. receives funding from AstraZeneca and Novartis. All other authors declare no conflicts of interest.
The authors thank the staff in the Central Services, the Histology Service, the Molecular Technology and Reagent Services, the Transgenic Technology Laboratory, and the Biological Services Unit at the Cancer Research UK Beatson Institute for their technical expertise and support (Cancer Research UK core grant, A17196). We are also grateful to Catherine Winchester for assistance with editing the manuscript. O.J.S. and his lab members were supported by grants from Cancer Research UK (A21139, A12481, A17196, A29055, C7932/A26825), the European Research Council (Starting Grant, 311301), and Pancreatic Cancer UK (Future Leaders Academy studentship; S.F.). G.J.I. was supported by Cancer Research UK (A29802). The Stratification in Colorectal Cancer (S:CORT) consortium was funded by the Medical Research Council and Cancer Research UK (grant award no MR/M016587/1). S.T. was supported as a 375 Senior Clinical Investigator by the Research Foundation—Flanders (FWO). J.D.G.L. was supported by a Medical Research Council Clinical Research Training Fellowship (MR/N021800/1). R.J. was funded by the Marie Skłodowska-Curie Actions Individual Fellowship (European Research Council, 659666).
© 2021, The Author(s).
Copyright 2021 Elsevier B.V., All rights reserved.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)