Apc-mutant cells deploy Notum to bias clonal competition and drive tumorigenesis

Dustin J Flanagan, Ann C Williams, Owen J Sampson, et al.

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The APC tumour suppressor is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells (ISCs) drives adenoma formation in mice via increased Wnt signalling 1, but reduced Wnt-ligand secretion surprisingly increases the ability of Apc-mutant ISCs to colonise a crypt (fixation) 2. Here, we investigate how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We find that Apc-mutant cells are enriched for transcripts encoding several secreted Wnt antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppresses the growth of wild-type organoids in a Notum-dependent manner. Furthermore, Notum-secreting Apc-mutant clones actively inhibit the proliferation of surrounding wild-type crypt cells and drive their differentiation, thereby outcompeting them from the niche. Importantly, genetic or pharmacological inhibition of Notum abrogates the ability of Apc-mutant cells to expand and form intestinal adenomas. Taken together, we identify Notum as a key mediator during the early stages of mutation fixation, which can be targeted to restore wild-type cell competitiveness, thus, offering novel preventative strategies for high-risk patients.
Original languageEnglish
JournalNature
Publication statusAccepted/In press - 7 Apr 2021

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