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.
Journal article
Nature communications
06/2021
12
Cancer Research UK Beatson Institute, Glasgow, UK.
S:CORT consortium, Colon, Spheroids, Cellular, Epithelial Cells, Fetus, Animals, Mice, Inbred C57BL, Colonic Neoplasms, Inflammation, Proto-Oncogene Proteins B-raf, Transforming Growth Factor beta, Adaptor Proteins, Signal Transducing, Receptors, Transforming Growth Factor beta, Transcription Factors, Prognosis, Signal Transduction, Cell Differentiation, Cell Survival, MAP Kinase Signaling System, Mutation, Wnt Proteins, Kaplan-Meier Estimate, Wnt Signaling Pathway, Carcinogenesis, Receptor, Transforming Growth Factor-beta Type I, YAP-Signaling Proteins