Faculty, Staff and Student Publications
Publication Date
6-3-2024
Journal
Developmental Cell
DOI
10.1016/j.devcel.2024.03.020
PMID
38574731
PMCID
PMC11379129
PubMedCentral® Posted Date
6-3-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
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.
Keywords
Animals, Mice, Telomere, Adenomatous Polyposis Coli Protein, Stem Cells, Enhancer of Zeste Homolog 2 Protein, Adenoma, Intestines, Cell Differentiation, Humans, Glycogen Synthase Kinase 3 beta, DNA Damage, Mice, Inbred C57BL, Wnt Signaling Pathway
Published Open-Access
yes
Recommended Citation
LaBella, Kyle A; Hsu, Wen-Hao; Li, Jiexi; et al., "Telomere Dysfunction Alters Intestinal Stem Cell Dynamics To Promote Cancer" (2024). Faculty, Staff and Student Publications. 4766.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4766
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