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)

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: Leach, Dr Joshua and Nixon, Mr Colin and Gay, David and Clark, Mr William and Ridgway, Dr Rachel and Bird, Dr Thomas and Sansom, Professor Owen and Hodder, Michael and Campbell, Dr Andrew
• 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 > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
58094	7	MRC Doctoral Training Grant 2011-2015	Mary Beth Kneafsey	Medical Research Council (MRC)	MR/J50032X/1	VPO VICE PRINCIPAL RESEARCH & ENTERPRISE
71654	1	Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancer	Owen Sansom	Medical Research Council (MRC)	MR/N021800/1	ICS - BEATSON INSTITUTE FOR CANCER RES.