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

S:CORT Consortium, Andrew Beggs

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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.

Original languageEnglish
Article number3464
Number of pages15
JournalNature Communications
Volume12
Issue number1
Early online date8 Jun 2021
DOIs
Publication statusPublished - Dec 2021

Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Carcinogenesis/metabolism
  • Cell Differentiation
  • Cell Survival
  • Colon/pathology
  • Colonic Neoplasms/genetics
  • Epithelial Cells/metabolism
  • Fetus/pathology
  • Inflammation/pathology
  • Kaplan-Meier Estimate
  • MAP Kinase Signaling System
  • Mice, Inbred C57BL
  • Mutation
  • Prognosis
  • Proto-Oncogene Proteins B-raf/genetics
  • Receptor, Transforming Growth Factor-beta Type I/metabolism
  • Receptors, Transforming Growth Factor beta/metabolism
  • Signal Transduction
  • Spheroids, Cellular/metabolism
  • Transcription Factors/metabolism
  • Transforming Growth Factor beta/metabolism
  • Wnt Proteins/metabolism
  • Wnt Signaling Pathway

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