학술논문
Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis.
Document Type
Academic Journal
Author
Leach JDG; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.; Vlahov N; Cancer Research UK Beatson Institute, Glasgow, UK.; Tsantoulis P; Department of Medical Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland.; Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.; Ridgway RA; Cancer Research UK Beatson Institute, Glasgow, UK.; Flanagan DJ; Cancer Research UK Beatson Institute, Glasgow, UK.; Gilroy K; Cancer Research UK Beatson Institute, Glasgow, UK.; Sphyris N; Cancer Research UK Beatson Institute, Glasgow, UK.; Vázquez EG; Gastrointestinal Stem Cell Biology Lab, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.; Vincent DF; Cancer Research UK Beatson Institute, Glasgow, UK.; Faller WJ; Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Hodder MC; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.; Raven A; Cancer Research UK Beatson Institute, Glasgow, UK.; Fey S; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.; Najumudeen AK; Cancer Research UK Beatson Institute, Glasgow, UK.; Strathdee D; Cancer Research UK Beatson Institute, Glasgow, UK.; Nixon C; Cancer Research UK Beatson Institute, Glasgow, UK.; Hughes M; Cancer Research UK Beatson Institute, Glasgow, UK.; Clark W; Cancer Research UK Beatson Institute, Glasgow, UK.; Shaw R; Cancer Research UK Beatson Institute, Glasgow, UK.; van Hooff SR; Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.; Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands.; Huels DJ; Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.; Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands.; Medema JP; Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.; Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands.; Barry ST; Bioscience, Early Oncology, AstraZeneca, Cambridge, UK.; Frame MC; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.; Unciti-Broceta A; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.; Leedham SJ; Gastrointestinal Stem Cell Biology Lab, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.; Inman GJ; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.; Jackstadt R; Cancer Research UK Beatson Institute, Glasgow, UK.; Thompson BJ; EMBL Australia, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.; Campbell AD; Cancer Research UK Beatson Institute, Glasgow, UK.; Tejpar S; Molecular Digestive Oncology, Department of Oncology, University of Leuven, Leuven, Belgium.; Sansom OJ; Cancer Research UK Beatson Institute, Glasgow, UK. o.sansom@beatson.gla.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. o.sansom@beatson.gla.ac.uk.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
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.