Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Leach, J. D.G. et al. (2021) Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nature Communications, 12, 3464. (doi: 10.1038/s41467-021-23717-5) (PMID:34103493) (PMCID:PMC8187652)

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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.

Item Type:Articles
Additional Information: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).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fey, Sigrid and Inman, Professor Gareth and Hughes, Mr Mark and Leach, Dr Joshua and Ridgway, Dr Rachel and Clark, Mr William and Strathdee, Dr Douglas and Hodder, Michael and Faller, Dr William and Vincent, Dr David and Sansom, Professor Owen and Campbell, Dr Andrew and Nixon, Mr Colin and Gilroy, Dr Kathryn
Authors: Leach, J. D.G., Vlahov, N., Tsantoulis, P., Ridgway, R. A., Flanagan, D. J., Gilroy, K., Sphyris, N., Vázquez, E. G., Vincent, D. F., Faller, W. J., Hodder, M. C., Raven, A., Fey, S., Najumudeen, A. K., Strathdee, D., Nixon, C., Hughes, M., Clark, W., Shaw, R., van Hooff, S. R., Huels, D. J., Medema, J. P., Barry, S. T., Frame, M., Unciti-Broceta, A., Leedham, S. J., Inman, G. J., Jackstadt, R., Thompson, B. J., Campbell, A. D., Tejpar, S., Sansom, O. J., Maughan, T., Salto-Tellez, M., Quirke, P., Koelzer, V., Dunne, P., Beggs, A., Campbell, P., Buffa, F., Holmes, C., Kaplan, R., Brown, L., Lawler, M., Hordern, J., Tomlinson, I., Leedham, S., and Morton, D.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12: 3464
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301989ACRClerate: Colorectal Cancer Stratified Medicine NetworkOwen SansomCancer Research UK (CRUK)C7932/A26825CS - Beatson Institute for Cancer Research
172879Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancerOwen SansomMedical Research Council (MRC)MR/N021800/1CS - Beatson Institute for Cancer Research