Loss of N-WASP drives early progression in an Apc model of intestinal tumourigenesis

Morris, H. T., Fort, L., Spence, H. J., Patel, R., Vincent, D. F., Park, J. H. , Snapper, S. B., Carey, F. A., Sansom, O. J. and Machesky, L. M. (2018) Loss of N-WASP drives early progression in an Apc model of intestinal tumourigenesis. Journal of Pathology, 245(3), pp. 337-348. (doi: 10.1002/path.5086) (PMID:29672847) (PMCID:PMC6033012)

Abstract

N‐WASP (WASL) is a widely expressed cytoskeletal signalling and scaffold protein also implicated in regulation of Wnt signalling and homeostatic maintenance of skin epithelial architecture. N‐WASP mediates invasion of cancer cells in vitro and its depletion reduces invasion and metastatic dissemination of breast cancer. Given this role in cancer invasion and universal expression in the gastrointestinal tract, we explored a role for N‐WASP in the initiation and progression of colorectal cancer. While deletion of N‐wasp is not detectably harmful in the murine intestinal tract, numbers of Paneth cells increased, indicating potential changes in the stem cell niche and migration up the crypt‐villus axis was enhanced. Loss of N‐wasp promoted adenoma formation in an adenomatous polyposis coli (Apc) deletion model of intestinal tumourigenesis. Thus, we establish a tumour suppressive role of N‐WASP in early intestinal carcinogenesis despite its later pro‐invasive role in other cancers. Our study highlights that while the actin cytoskeletal machinery promotes invasion of cancer cells, it also maintains normal epithelial tissue function and thus may have tumour suppressive roles in pre‐neoplastic tissues.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Park, Mr James and Spence, Dr Heather and Machesky, Professor Laura and Morris, Dr Hayley and Patel, Dr Rachana and Fort, Loic and Vincent, Dr David and Sansom, Professor Owen
• Authors: Morris, H. T., Fort, L., Spence, H. J., Patel, R., Vincent, D. F., Park, J. H., Snapper, S. B., Carey, F. A., Sansom, O. J., and Machesky, L. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Pathology
• Publisher: Wiley
• ISSN: 0022-3417
• ISSN (Online): 1096-9896
• Published Online: 19 April 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Journal of Pathology 245(3): 337-348
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
62029	1	Investigating the role of N-WASP in the development and metastasis of colorectal cancer (SCP3 Fellowship 2012)	Laura Machesky	Medical Research Council (MRC)	G1000419	ICS - BEATSON INSTITUTE FOR CANCER RES.