| Title: |
Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis |
| Authors: |
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; van Hooff, SR; Huels, DJ; Medema, JP; Barry, ST; Frame, MC; Unciti-Broceta, A; Leedham, SJ |
| Publisher Information: |
Nature Research |
| Publication Year: |
2026 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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 |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1038/s41467-021-23717-5 |
| Availability: |
https://doi.org/10.1038/s41467-021-23717-5; https://ora.ox.ac.uk/objects/uuid:145e681a-446e-4748-97ff-7d7731fd3000 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.C404BE87 |
| Database: |
BASE |