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

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. Bird and Owen J. Sansom ()
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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
Andrew D. Campbell: Cancer Research UK Beatson Institute
Thomas G. Bird: Cancer Research UK Beatson Institute
Owen J. Sansom: Cancer Research UK Beatson Institute

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08586-3

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