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Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.
- Source :
-
Developmental cell [Dev Cell] 2024 Jun 03; Vol. 59 (11), pp. 1475-1486.e5. Date of Electronic Publication: 2024 Apr 03. - Publication Year :
- 2024
-
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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Enhancer of Zeste Homolog 2 Protein metabolism
Enhancer of Zeste Homolog 2 Protein genetics
Adenoma pathology
Adenoma genetics
Adenoma metabolism
Intestines pathology
Cell Differentiation
Humans
Glycogen Synthase Kinase 3 beta metabolism
Glycogen Synthase Kinase 3 beta genetics
DNA Damage
Mice, Inbred C57BL
Wnt Signaling Pathway
Telomere metabolism
Adenomatous Polyposis Coli Protein genetics
Adenomatous Polyposis Coli Protein metabolism
Stem Cells metabolism
Stem Cells pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1551
- Volume :
- 59
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Developmental cell
- Publication Type :
- Academic Journal
- Accession number :
- 38574731
- Full Text :
- https://doi.org/10.1016/j.devcel.2024.03.020