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

Gay, D. M. et al. (2019) Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nature Communications, 10, 723. (doi:10.1038/s41467-019-08586-3) (PMID:30760720) (PMCID:PMC6374445)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Campbell, Mr Andrew and Bird, Dr Thomas and Leach, Dr Joshua and Nixon, Mr Colin and Ridgway, Dr Rachel and Clark, Mr William and Hodder, Michael and Gay, David and Sansom, Professor Owen
Authors: Gay, D. M., Ridgway, R. A., Müeller, M., Hodder, M. C., Hedley, A., Clark, W., Leach, J. D., Jackstadt, R., Nixon, C., Huels, D. J., Campbell, A. D., Bird, T. G., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Nature Communications 10(1):723
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
580947MRC Doctoral Training Grant 2011-2015Mary Beth KneafseyMedical Research Council (MRC)MR/J50032X/1VPO VICE PRINCIPAL RESEARCH & ENTERPRISE
716541Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancerOwen SansomMedical Research Council (MRC)MR/N021800/1ICS - BEATSON INSTITUTE FOR CANCER RES.