Telomere dysfunction alters intestinal stem cell dynamics to promote cancer

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3β inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres. [Display omitted] •Telomere dysfunction augments intestinal tumor initiation•DNA damage represses EZH2, upregulating Wnt antagonist expression•Elevated Wnt antagonists impair adjacent normal stem cell growth•Boosting Wnt signaling in normal stem cells reduces clonal expansion LaBella et al. address a long-standing question as to how telomere dysfunction accelerates intestinal tumor initiation and demonstrate the interrelationship of telomere dysfunction, EZH2, and Wnt signaling in early tumorigenesis. These mechanistic insights define an interception strategy to quell the tumor-initiating potential of APC-mutant cells with shortened telomeres.