Oncogenic BRAF, Unrestrained by TGFβ-receptor Signalling, Drives Right-sided Colonic Tumorigenesis

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jun 9

PMID 34103493

Citations 33

Authors

Joshua D G Leach

Nikola Vlahov

Petros Tsantoulis

Rachel A Ridgway

Dustin J Flanagan

Kathryn Gilroy

Nathalie Sphyris

Ester G Vazquez

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 van 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

Owen J Sansom

Affiliations

Soon will be listed here.

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.

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