Chromosomal instability drives metastasis through a cytosolic DNA response

Samuel F. Bakhoum, Bryan Ngo, Ashley M. Laughney, Julie Ann Cavallo, Charles J. Murphy, Peter Ly, Pragya Shah, Roshan K. Sriram, Thomas B.K. Watkins, Neil K. Taunk, Mercedes Duran, Chantal Pauli, Christine Shaw, Kalyani Chadalavada, Vinagolu K. Rajasekhar, Giulio Genovese, Subramanian Venkatesan, Nicolai J. Birkbak, Nicholas McGranahan, Mark LundquistQuincey 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

Research output: Contribution to journalArticle

212 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)467-472
Number of pages6
JournalNature
Volume553
Issue number7689
DOIs
StatePublished - Jan 25 2018

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Chromosomal instability drives metastasis through a cytosolic DNA response'. Together they form a unique fingerprint.

Cite this