| First Author | Leach JDG | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 3464 |
| PubMed ID | 34103493 | Mgi Jnum | J:307911 |
| Mgi Id | MGI:6725397 | Doi | 10.1038/s41467-021-23717-5 |
| Citation | Leach JDG, et al. (2021) Oncogenic BRAF, unrestrained by TGFbeta-receptor signalling, drives right-sided colonic tumorigenesis. Nat Commun 12(1):3464 |
| abstractText | 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 TGFbeta signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFbeta-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 TGFbeta-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells. |
