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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 publication

DOI

10.1038/s41467-021-23717-5

Type

Journal article

Journal

Nat Commun

Publication Date

08/06/2021

Volume

12

Keywords

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