Journal
NATURE
Volume 553, Issue 7689, Pages 467-+Publisher
NATURE RESEARCH
DOI: 10.1038/nature25432
Keywords
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Categories
Funding
- DoD Breast Cancer Research Breakthrough Award (BCRBA) [W81XWH-16-1-0315]
- Elsa Pardee Foundation
- MSKCC Cytogenetics Core [P30-CA008748]
- NSF Graduate Research Fellowship [DGE1257284]
- NIH [R01-HL082792, U54-CA210184, R35-CA197588]
- DoD BCRBA [BC150580, W81XWH-16-1-0316]
- NSF [CBET-1254846]
- NCI [K99-CA218871]
- Breast Cancer Research Foundation
- Gray Foundation Basser Initiative
- Cancer Research UK [19310, 17786, 20466] Funding Source: researchfish
- Medical Research Council [MR/P014712/1, G0701935] Funding Source: researchfish
- Rosetrees Trust [M445, M179, M640, M231-CD1, M391] Funding Source: researchfish
- The Francis Crick Institute [A1278, C60895/A23896, 10485, 10169, 10170, C28575/A25223, VEG 108844, 10467, 10172, 10359] Funding Source: researchfish
- CDMRP [BC150580, 893161] Funding Source: Federal RePORTER
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1254846] Funding Source: National Science Foundation
- MRC [G0701935, MR/P014712/1] Funding Source: UKRI
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Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-kappa B signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.
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