Chromosomal instability drives metastasis through a cytosolic DNA response

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. In chromosomally unstable tumour cells, rupture of micronuclei exposes genomic DNA and activates the cGAS–STING cytosolic DNA-sensing pathway, thereby promoting metastasis. The cGAS–STING cytosolic DNA-sensing pathway detects the presence of double-stranded DNA in the cytosol of cells, which triggers an inflammatory response. This pathway can be activated by foreign or cellular DNA. Lewis Cantley and colleagues show that the pathway is activated in human cancer cells with chromosomal instability. Improper segregation of chromosomes during cell division leads to the formation of unstable micronuclei, which burst and release their DNA into the cytosol. The resulting inflammatory response involves activation of NF-κB signalling and promotes metastasis in a STING-dependent manner. These findings link chromosomal instability to metastasis and may offer new avenues to preventing the spread of cancer to distant organs.