Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features
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Published:2022-12-07
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Flanagan Dustin J.ORCID, Amirkhah RahelehORCID, Vincent David F., Gunduz Nuray, Gentaz Pauline, Cammareri Patrizia, McCooey Aoife J., McCorry Amy M. B., Fisher Natalie C., Davis Hayley L.ORCID, Ridgway Rachel A.ORCID, Lohuis Jeroen, Leach Joshua D. G., Jackstadt Rene, Gilroy Kathryn, Mariella Elisa, Nixon ColinORCID, Clark William, Hedley AnnORCID, Markert Elke K., Strathdee DouglasORCID, Bartholin LaurentORCID, Redmond Keara L., Kerr Emma M.ORCID, Longley Daniel B., Ginty Fiona, Cho Sanghee, Coleman Helen G., Loughrey Maurice B., Bardelli AlbertoORCID, Maughan Timothy S., Campbell Andrew D.ORCID, Lawler Mark, Leedham Simon J., Barry Simon T.ORCID, Inman Gareth J.ORCID, van Rheenen JaccoORCID, Dunne Philip D.ORCID, Sansom Owen J.ORCID
Abstract
AbstractThe pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC’s with born to be bad traits.
Funder
Cancer Research UK RCUK | Medical Research Council
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference77 articles.
1. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021). 2. Arnold, M. et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 66, 683–691 (2017). 3. Logan, R. F. et al. Outcomes of the bowel cancer screening programme (BCSP) in England after the first 1 million tests. Gut 61, 1439–1446 (2012). 4. Morris, E. J. et al. Surgical management and outcomes of colorectal cancer liver metastases. Br. J. Surg. 97, 1110–1118 (2010). 5. Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996). [pii].
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