Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

Flanagan, D. J. et al. (2022) Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features. Nature Communications, 13, 7551. (doi: 10.1038/s41467-022-35134-3) (PMID:36477656) (PMCID:PMC9729215)

Abstract

The 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.

• Item Type: Articles

Additional Information

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 and UK Medical Research Council programme (S:CORT MR/M016587/1), the NI HSC R&D
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• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dunne, Dr Philip and Gilroy, Dr Kathryn and Leach, Dr Joshua and Cammareri, Dr Patrizia and Nixon, Mr Colin and Markert, Dr Elke and Clark, Mr William and Vincent, Dr David and Strathdee, Mr Douglas and Ridgway, Dr Rachel and Inman, Professor Gareth and Flanagan, Dr Dustin and Sansom, Professor Owen and Campbell, Dr Andrew
• Authors: Flanagan, D. J., Amirkhah, R., Vincent, D. F., Gundaz, N., Gentaz, P., Cammareri, P., McCooey, A. J., McCorry, A. M. B., Fisher, N. C., Davis, H. L., Ridgway, R. A., Lohuis, J., Leach, J. D.G., Jackstadt, R., Gilroy, K., Mariella, E., Nixon, C., Clark, W., Hedley, A., Markert, E. K., Strathdee, D., Bartholin, L., Redmond, K. L., Kerr, E. M., Longley, D. B., Ginty, F., Cho, S., Coleman, H. G., Loughrey, M. B., Bardelli, A., Maughan, T. S., Campbell, A. D., Lawler, M., Leedham, S. J., Barry, S. T., Inman, G. J., van Rheenen, J., Dunne, P. D., and Sansom, O. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Communications 13: 7551
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172879		Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancer	Owen Sansom	Medical Research Council (MRC)	MR/N021800/1	CS - Beatson Institute for Cancer Research
301989		ACRClerate: Colorectal Cancer Stratified Medicine Network	Owen Sansom	Cancer Research UK (CRUK)	C7932/A26825	CS - Beatson Institute for Cancer Research
315691		Using complex state of the art mouse models of cancer to improve the understanding and treatment of human cancer	Karen Blyth	Medical Research Council (MRC)	MC_PC_21042	CS - Beatson Institute for Cancer Research