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

Research output: Contribution to journalArticlepeer-review

Authors

Colleges, School and Institutes

External organisations

  • Beatson West Scotland Cancer Centre
  • University of Geneva
  • Oxford University Hospitals NHS Foundation Trust
  • The Netherlands Cancer Institute
  • Department of Medical Oncology, Academic Medical Center
  • Aytu BioScience
  • University of Edinburgh
  • Australian National University
  • Division PMA (Production Engineering), University of Leuven (KU Leuven)

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.

Details

Original languageEnglish
Article number3464
Number of pages15
JournalNature Communications
Volume12
Issue number1
Early online date8 Jun 2021
Publication statusE-pub ahead of print - 8 Jun 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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