Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer.
Journal
Nature materials
ISSN: 1476-4660
Titre abrégé: Nat Mater
Pays: England
ID NLM: 101155473
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
25
08
2021
accepted:
02
11
2022
medline:
5
5
2023
pubmed:
30
12
2022
entrez:
29
12
2022
Statut:
ppublish
Résumé
The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.
Identifiants
pubmed: 36581770
doi: 10.1038/s41563-022-01431-x
pii: 10.1038/s41563-022-01431-x
pmc: PMC10156599
doi:
Substances chimiques
Actins
0
DNA
9007-49-2
Nucleotidyltransferases
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
644-655Commentaires et corrections
Type : ErratumIn
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
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