Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In -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 -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 -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 -mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human -mutant cancers with shortened telomeres.

中文翻译：

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端粒功能障碍改变肠道干细胞动力学促进癌症

端粒动态与衰老特征有关，与年龄相关的端粒丢失会促进上皮癌的发展。在Apc突变小鼠中，与端粒功能障碍相关的DNA损伤的发生已被证明可通过未知机制加速腺瘤的发生。在这里，我们观察到，经过改造而经历端粒功能障碍的Apc突变小鼠表现出由于细胞竞争增强和克隆扩张而加速腺瘤形成。从机制上讲，端粒功能障碍会诱导 EZH2 的抑制，从而导致 Wnt 拮抗剂的去抑制，从而导致邻近干细胞的分化，并相对于Apc缺陷的端粒功能障碍细胞具有相对生长优势。相应地，在该小鼠模型中，GSK3β抑制抵消了Wnt拮抗剂对肠干细胞的作用，导致端粒功能障碍的Apc突变细胞的腺瘤形成受损。因此，端粒功能障碍通过改变干细胞动力学导致癌症发生，从而确定了端粒缩短的人类APC突变癌症的拦截策略。