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Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer

Author

Listed:
  • David M. Gay

    (Cancer Research UK Beatson Institute)

  • Rachel A. Ridgway

    (Cancer Research UK Beatson Institute)

  • Miryam Müller

    (Cancer Research UK Beatson Institute)

  • Michael C. Hodder

    (Cancer Research UK Beatson Institute)

  • Ann Hedley

    (Cancer Research UK Beatson Institute)

  • William Clark

    (Cancer Research UK Beatson Institute)

  • Joshua D. Leach

    (Cancer Research UK Beatson Institute)

  • Rene Jackstadt

    (Cancer Research UK Beatson Institute)

  • Colin Nixon

    (Cancer Research UK Beatson Institute)

  • David J. Huels

    (Cancer Research UK Beatson Institute
    University of Amsterdam)

  • Andrew D. Campbell

    (Cancer Research UK Beatson Institute)

  • Thomas G. Bird

    (Cancer Research UK Beatson Institute
    University of Glasgow
    University of Edinburgh)

  • Owen J. Sansom

    (Cancer Research UK Beatson Institute
    University of Glasgow)

Abstract

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt–driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08586-3
    DOI: 10.1038/s41467-019-08586-3
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    Cited by:

    1. 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.
    2. Hongyang Wang & Mariann Bienz & Xiao-Xue Yan & Wenqing Xu, 2023. "Structural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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