Chromosomal instability drives metastasis through a cytosolic DNA response.

TitleChromosomal instability drives metastasis through a cytosolic DNA response.
Publication TypeJournal Article
Year of Publication2018
AuthorsBakhoum SF, Ngo B, Laughney AM, Cavallo J-A, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK, Duran M, Pauli C, Shaw C, Chadalavada K, Rajasekhar VK, Genovese G, Venkatesan S, Birkbak NJ, McGranahan N, Lundquist M, LaPlant Q, Healey JH, Elemento O, Chung CH, Lee NY, Imielenski M, Nanjangud G, Pe'er D, Cleveland DW, Powell SN, Lammerding J, Swanton C, Cantley LC
Date Published2018 01 25
KeywordsAnimals, Brain Neoplasms, Breast Neoplasms, Carcinoma, Squamous Cell, Cell Line, Chromosomal Instability, Chromosome Segregation, Cytosol, DNA, Neoplasm, Female, Head and Neck Neoplasms, Humans, Inflammation, Membrane Proteins, Mesoderm, Mice, Micronuclei, Chromosome-Defective, Neoplasm Metastasis, NF-kappa B, Nucleotidyltransferases, Xenograft Model Antitumor Assays

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-κB 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.

Alternate JournalNature
PubMed ID29342134
PubMed Central IDPMC5785464
Grant ListG0701935 / / Medical Research Council / United Kingdom
K99 CA218871 / CA / NCI NIH HHS / United States
U54 CA210184 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R35 CA197588 / CA / NCI NIH HHS / United States
R01 CA187069 / CA / NCI NIH HHS / United States
R01 CA169306 / CA / NCI NIH HHS / United States
R35 GM122476 / GM / NIGMS NIH HHS / United States
R01 HL082792 / HL / NHLBI NIH HHS / United States