eprintid: 10130448 rev_number: 16 eprint_status: archive userid: 608 dir: disk0/10/13/04/48 datestamp: 2021-07-01 19:48:16 lastmod: 2021-12-11 00:03:35 status_changed: 2021-07-01 19:48:16 type: article metadata_visibility: show creators_name: Leach, JDG creators_name: Vlahov, N creators_name: Tsantoulis, P creators_name: Ridgway, RA creators_name: Flanagan, DJ creators_name: Gilroy, K creators_name: Sphyris, N creators_name: Vázquez, EG creators_name: Vincent, DF creators_name: Faller, WJ creators_name: Hodder, MC creators_name: Raven, A creators_name: Fey, S creators_name: Najumudeen, AK creators_name: Strathdee, D creators_name: Nixon, C creators_name: Hughes, M creators_name: Clark, W creators_name: Shaw, R creators_name: S:CORT consortium, creators_name: van Hooff, SR creators_name: Huels, DJ creators_name: Medema, JP creators_name: Barry, ST creators_name: Frame, MC creators_name: Unciti-Broceta, A creators_name: Leedham, SJ creators_name: Inman, GJ creators_name: Jackstadt, R creators_name: Thompson, BJ creators_name: Campbell, AD creators_name: Tejpar, S creators_name: Sansom, OJ title: Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. ispublished: pub divisions: UCL divisions: B02 divisions: D65 divisions: J38 keywords: Adaptor Proteins, Signal Transducing, Animals, Carcinogenesis, Cell Differentiation, Cell Survival, Colon, Colonic Neoplasms, Epithelial Cells, Fetus, Inflammation, Kaplan-Meier Estimate, MAP Kinase Signaling System, Mice, Inbred C57BL, Mutation, Prognosis, Proto-Oncogene Proteins B-raf, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Signal Transduction, Spheroids, Cellular, Transcription Factors, Transforming Growth Factor beta, Wnt Proteins, Wnt Signaling Pathway note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. abstract: 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. date: 2021-06-08 date_type: published official_url: https://doi.org/10.1038/s41467-021-23717-5 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1872735 doi: 10.1038/s41467-021-23717-5 pii: 10.1038/s41467-021-23717-5 lyricists_name: Brown, Louise lyricists_name: Kaplan, Richard lyricists_id: LCBRO59 lyricists_id: RKAPL47 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Nature Communications volume: 12 article_number: 3464 event_location: England citation: Leach, JDG; Vlahov, N; Tsantoulis, P; Ridgway, RA; Flanagan, DJ; Gilroy, K; Sphyris, N; ... Sansom, OJ; + view all <#> 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; 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; - view fewer <#> (2021) Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nature Communications , 12 , Article 3464. 10.1038/s41467-021-23717-5 <https://doi.org/10.1038/s41467-021-23717-5>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10130448/1/s41467-021-23717-5.pdf