Telomere dysfunction alters intestinal stem cell dynamics to promote cancer

• DOI: 10.1016/j.devcel.2024.03.020
• Publication Date: 2024-04-03T14:40:05Z
• Authors: Kyle A. LaBella; Wen-Hao Hsu; Jiexi Li; Yutao Qi; Yonghong Liu; Jingjing Liu; Chia-Chin Wu; Yang Liu; Zingzhi Song; Yiyun Lin; Jonathan M. Blecher; Shan Jiang; Xiaoying Shang; Jincheng Han; Denise J. Spring; Jianhua Zhang; Yan Xia; Ronald A. DePinho
• Keywords: Adenoma; Glycogen Synthase Kinase 3 beta; Stem Cells; Adenomatous Polyposis Coli Protein; Cell Differentiation; Telomere; Intestines; Mice, Inbred C57BL; Mice; Animals; Humans; Enhancer of Zeste Homolog 2 Protein; Wnt Signaling Pathway; DNA Damage

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.