Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells

Huels, D.J. et al. (2018) Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells. Nature Communications, 9, 1132. (doi: 10.1038/s41467-018-03426-2) (PMID:29556067) (PMCID:PMC5859272)

Abstract

Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.

• Item Type: Articles
• Additional Information: The research was supported by Cancer Research UK core grant C596/A17196 and grant to OS A12481, and D.J.H. was funded by the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement number 278568. O.J.S. is funded by an ERC Starting grant COLONCAN under agreement number 311301. This work was financially supported by European Research Council Grant CANCERRECURRENCE 648804 (to J.v.R.), by the CancerGenomics.nl http://CancerGenomics.nl (Netherlands Organisation for Scientific Research) program (to J.v.R.), by the Doctor Josef Steiner Foundation (to J.v.R) and by the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement no. 642866 (to J.v.R).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cammareri, Dr Patrizia and Hodder, Michael and Solar Abboud, Dr Myriam and Zeiger, Lucas and Nixon, Mr Colin and Faller, Dr William and Ridgway, Dr Rachel and Sansom, Professor Owen and Campbell, Dr Andrew
• Authors: Huels, D.J., Bruens, L., Hodder, M.C., Cammareri, P., Campbell, A.D., Ridgway, R.A., Gay, D.M., Solar Abboud, M., Faller, W.J., Nixon, C., Zeiger, L.B., McLaughlin, M.E., Morrissey, E., Winton, D.J., Snippert, H.J., van Rheenen, J., 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 © 2018 The Authors
• First Published: First published in Nature Communications 9: 1132
• Publisher Policy: Reproduced under a Creative Commons License