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

• Published in: Nature communications Vol. 12; no. 1; pp. 3464 - 15
• Main Authors: Leach, Joshua D. G., Vlahov, Nikola, Tsantoulis, Petros, Ridgway, Rachel A., Flanagan, Dustin J., Gilroy, Kathryn, Sphyris, Nathalie, Vázquez, Ester G., Vincent, David F., Faller, William J., Hodder, Michael C., Raven, Alexander, Fey, Sigrid, Najumudeen, Arafath K., Strathdee, Douglas, Nixon, Colin, Hughes, Mark, Clark, William, Shaw, Robin, van Hooff, Sander R., Huels, David J., Medema, Jan Paul, Barry, Simon T., Frame, Margaret C., Unciti-Broceta, Asier, Leedham, Simon J., Inman, Gareth J., Jackstadt, Rene, Thompson, Barry J., Campbell, Andrew D., Tejpar, Sabine, Sansom, Owen J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 38/91; 631/67/70; 631/67/71; 64/60; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antibiotics; Ataxin; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Differentiation; Cell Survival; Colon; Colon - pathology; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Colorectal carcinoma; Epithelial Cells - metabolism; Fetus - pathology; Humanities and Social Sciences; Inflammation; Inflammation - pathology; Kaplan-Meier Estimate; MAP kinase; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Microorganisms; Mismatch repair; multidisciplinary; Mutants; Mutation; Phenotypes; Progenitor cells; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Receptor, Transforming Growth Factor-beta Type I - metabolism; Receptors; Receptors, Transforming Growth Factor beta - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stem cells; Transcription activation; Transcription Factors - metabolism; Transforming Growth Factor beta - metabolism; Tumorigenesis; Tumors; Wnt Proteins - metabolism; Wnt Signaling Pathway; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23717-5

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. Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype.