Chromosomal instability drives metastasis through a cytosolic DNA responseMore about Open Access at the Crick
Authors listSamuel F Bakhoum Bryan Ngo Ashley M Laughney Julie-Ann Cavallo Charles J Murphy Peter Ly Pragya Shah Roshan K Sriram Tom Watkins Neil K Taunk Mercedes Duran Chantal Pauli Christine Shaw Kalyani Chadalavada Vinagolu K Rajasekhar Giulio Genovese Subramanian Venkatesan Nicolai Birkbak Nicholas McGranahan Mark Lundquist Quincey LaPlant John H Healey Olivier Elemento Christine H Chung Nancy Y Lee Marcin Imielenski Gouri Nanjangud Dana Pe'er Don W Cleveland Simon N Powell Jan Lammerding Charles Swanton Lewis C Cantley
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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-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.
Issue number 7689