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-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.

Keywords

MeSH Terms

Affiliated Institutions

• CRUK Lung Cancer Centre of Excellence GB
• Moffitt Cancer Center US
• Ludwig Cancer Research US
• Cornell University US
• Broad Institute US
• Memorial Sloan Kettering Cancer Center US
• Weill Cornell Medicine US
• University Hospital of Zurich CH
• The Francis Crick Institute GB
• University College London GB
• University of California, San Diego US

Related Publications