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

Leach JDG., Vlahov N., Tsantoulis P., Ridgway RA., Flanagan DJ., Gilroy K., Sphyris N., Vázquez EG., Vincent DF., Faller WJ., Hodder MC., Raven A., Fey S., Najumudeen AK., Strathdee D., Nixon C., Hughes M., Clark W., Shaw R., S:CORT consortium None., van Hooff SR., Huels DJ., Medema JP., Barry ST., Frame MC., Unciti-Broceta A., Leedham SJ., Inman GJ., Jackstadt R., Thompson BJ., Campbell AD., Tejpar S., Sansom OJ.

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.

DOI

10.1038/s41467-021-23717-5

Type

Journal article

Journal

Nature communications

Publication Date

06/2021

Volume

12

Addresses

Cancer Research UK Beatson Institute, Glasgow, UK.

Keywords

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

Permalink Original publication