Chromosomal instability drives metastasis through a cytosolic DNA response Journal Article
| Authors: | Bakhoum, S. F.; Ngo, B.; Laughney, A. M.; Cavallo, J. A.; Murphy, C. J.; Ly, P.; Shah, P.; Sriram, R. K.; Watkins, T. B. K.; Taunk, N. K.; Duran, M.; Pauli, C.; Shaw, C.; Chadalavada, K.; Rajasekhar, V. K.; Genovese, G.; Venkatesan, S.; Birkbak, N. J.; McGranahan, N.; Lundquist, M.; LaPlant, Q.; Healey, J. H.; Elemento, O.; Chung, C. H.; Lee, N. Y.; Imielenski, M.; Nanjangud, G.; Pe'er, D.; Cleveland, D. W.; Powell, S. N.; Lammerding, J.; Swanton, C.; Cantley, L. C. |
| Article Title: | Chromosomal instability drives metastasis through a cytosolic DNA response |
| Abstract: | 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-? 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. |
| Keywords: | signal transduction; interferon; nonhuman; pathophysiology; genetic analysis; chromosome; disease association; metastasis; immunoglobulin enhancer binding protein; dna; gene repression; tumor cell; genomics; chromosomal instability; innate immunity; tumor model; tumor; aneuploidy; cell invasion; genomic dna; cytosol; chromosome segregation; cyclic gmp; epithelial mesenchymal transition; micronucleus; cell component; cancer; human; priority journal; article; extrachromosomal dna |
| Journal Title: | Nature |
| Volume: | 553 |
| Issue: | 7689 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-01-25 |
| Start Page: | 467 |
| End Page: | 472 |
| Language: | English |
| DOI: | 10.1038/nature25432 |
| PROVIDER: | scopus |
| PMCID: | PMC5785464 |
| PUBMED: | 29342134 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
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