3 years ago

Chromosomal instability drives metastasis through a cytosolic DNA response

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

Publisher URL: https://www.nature.com/articles/nature25432

DOI: 10.1038/nature25432

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