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

Dustin J. Flanagan (), Raheleh Amirkhah, David F. Vincent, Nuray Gunduz, Pauline Gentaz, Patrizia Cammareri, Aoife J. McCooey, Amy M. B. McCorry, Natalie C. Fisher, Hayley L. Davis, Rachel A. Ridgway, Jeroen Lohuis, Joshua D. G. Leach, Rene Jackstadt, Kathryn Gilroy, Elisa Mariella, Colin Nixon, William Clark, Ann Hedley, Elke K. Markert, Douglas Strathdee, Laurent Bartholin, Keara L. Redmond, Emma M. Kerr, Daniel B. Longley, Fiona Ginty, Sanghee Cho, Helen G. Coleman, Maurice B. Loughrey, Alberto Bardelli, Timothy S. Maughan, Andrew D. Campbell, Mark Lawler, Simon J. Leedham, Simon T. Barry, Gareth J. Inman, Jacco Rheenen, Philip D. Dunne and Owen J. Sansom ()
Additional contact information
Dustin J. Flanagan: Cancer Research UK Beatson Institute
Raheleh Amirkhah: Queen’s University Belfast
David F. Vincent: Cancer Research UK Beatson Institute
Nuray Gunduz: Cancer Research UK Beatson Institute
Pauline Gentaz: Cancer Research UK Beatson Institute
Patrizia Cammareri: Cancer Research UK Beatson Institute
Aoife J. McCooey: Queen’s University Belfast
Amy M. B. McCorry: Queen’s University Belfast
Natalie C. Fisher: Queen’s University Belfast
Hayley L. Davis: University of Oxford
Rachel A. Ridgway: Cancer Research UK Beatson Institute
Jeroen Lohuis: Oncode Institute, The Netherlands Cancer Institute
Joshua D. G. Leach: Cancer Research UK Beatson Institute
Rene Jackstadt: Cancer Research UK Beatson Institute
Kathryn Gilroy: Cancer Research UK Beatson Institute
Elisa Mariella: University of Torino
Colin Nixon: Cancer Research UK Beatson Institute
William Clark: Cancer Research UK Beatson Institute
Ann Hedley: Cancer Research UK Beatson Institute
Elke K. Markert: Cancer Research UK Beatson Institute
Douglas Strathdee: Cancer Research UK Beatson Institute
Laurent Bartholin: INSERM Centre de Recherche en Cancérologie de Lyon
Keara L. Redmond: Queen’s University Belfast
Emma M. Kerr: Queen’s University Belfast
Daniel B. Longley: Queen’s University Belfast
Fiona Ginty: GE Global Research Center
Sanghee Cho: GE Global Research Center
Helen G. Coleman: Queen’s University Belfast
Maurice B. Loughrey: Queen’s University Belfast
Alberto Bardelli: University of Torino
Timothy S. Maughan: University of Oxford
Andrew D. Campbell: Cancer Research UK Beatson Institute
Mark Lawler: Queen’s University Belfast
Simon J. Leedham: University of Oxford
Simon T. Barry: Bioscience, Oncology R&D, AstraZeneca
Gareth J. Inman: Cancer Research UK Beatson Institute
Jacco Rheenen: Oncode Institute, The Netherlands Cancer Institute
Philip D. Dunne: Cancer Research UK Beatson Institute
Owen J. Sansom: Cancer Research UK Beatson Institute

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-35134-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35134-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-35134-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().