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

Author

Listed:
  • Dustin J. Flanagan

    (Cancer Research UK Beatson Institute
    Monash University
    Monash University)

  • 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
    University of Glasgow)

  • Rene Jackstadt

    (Cancer Research UK Beatson Institute
    Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) and Deutsches Krebsforschungszentrum (DKFZ))

  • 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
    University of Newcastle upon Tyne)

  • Elke K. Markert

    (Cancer Research UK Beatson Institute
    University of Glasgow)

  • 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
    Queen’s University Belfast)

  • Maurice B. Loughrey

    (Queen’s University Belfast
    Queen’s University Belfast
    Belfast Health and Social Care Trust)

  • 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
    University of Glasgow)

  • Jacco Rheenen

    (Oncode Institute, The Netherlands Cancer Institute)

  • Philip D. Dunne

    (Cancer Research UK Beatson Institute
    Queen’s University Belfast)

  • Owen J. Sansom

    (Cancer Research UK Beatson Institute
    University of Glasgow)

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.

Suggested Citation

  • 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. R, 2022. "Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35134-3
    DOI: 10.1038/s41467-022-35134-3
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    References listed on IDEAS

    as
    1. Philip D. Dunne & Matthew Alderdice & Paul G. O'Reilly & Aideen C. Roddy & Amy M. B. McCorry & Susan Richman & Tim Maughan & Simon S. McDade & Patrick G. Johnston & Daniel B. Longley & Elaine Kay & Da, 2017. "Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    2. Claudio Isella & Francesco Brundu & Sara E. Bellomo & Francesco Galimi & Eugenia Zanella & Roberta Porporato & Consalvo Petti & Alessandro Fiori & Francesca Orzan & Rebecca Senetta & Carla Boccaccio &, 2017. "Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    3. Sandra Misale & Rona Yaeger & Sebastijan Hobor & Elisa Scala & Manickam Janakiraman & David Liska & Emanuele Valtorta & Roberta Schiavo & Michela Buscarino & Giulia Siravegna & Katia Bencardino & Andr, 2012. "Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer," Nature, Nature, vol. 486(7404), pages 532-536, June.
    4. David M. Gay & Rachel A. Ridgway & Miryam Müller & Michael C. Hodder & Ann Hedley & William Clark & Joshua D. Leach & Rene Jackstadt & Colin Nixon & David J. Huels & Andrew D. Campbell & Thomas G. Bir, 2019. "Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
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