NOTUM from Apc-mutant cells biases clonal competition to initiate cancer

Flanagan, D. J. et al. (2021) NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature, 594, pp. 430-435. (doi: 10.1038/s41586-021-03525-z) (PMID:34079124)

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Abstract

The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ridgway, Dr Rachel and Clark, Mr William and Hodder, Michael and Sansom, Professor Owen and Kirschner, Dr Kristina and Nixon, Mr Colin and Gilchrist, Ella and Gilroy, Dr Kathryn and McGarry, Ms Lynn
Authors: Flanagan, D. J., Pentinmikko, N., Luopajärvi, K., Willis, N. J., Gilroy, K., Raven, A. P., Mcgarry, L., Englund, J. I., Webb, A. T., Scharaw, S., Nasreddin, N., Hodder, M. C., Ridgway, R. A., Minnee, E., Sphyris, N., Gilchrist, E., Najumudeen, A. K., Romagnolo, B., Perret, C., Williams, A. C., Clevers, H., Nummela, P., Lähde, M., Alitalo, K., Hietakangas, V., Hedley, A., Clark, W., Nixon, C., Kirschner, K., Jones, E. Y., Ristimäki, A., Leedham, S. J., Fish, P. V., Vincent, J.-P., Katajisto, P., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature
Publisher:Nature Research
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:02 June 2021
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190394MRC Doctoral Training Grant 2011-2015Mary Beth KneafseyMedical Research Council (MRC)MR/J50032X/1Research and Innovation Services