Chromosomal instability drives metastasis through a cytosolic DNA response

Nature. 2018 Jan 25;553(7689):467-472. doi: 10.1038/nature25432. Epub 2018 Jan 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Breast Neoplasms / secondary
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Line
  • Chromosomal Instability* / genetics
  • Chromosome Segregation
  • Cytosol / enzymology
  • Cytosol / metabolism*
  • DNA, Neoplasm / metabolism*
  • Female
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Membrane Proteins / metabolism
  • Mesoderm / metabolism
  • Mice
  • Micronuclei, Chromosome-Defective
  • NF-kappa B / metabolism
  • Neoplasm Metastasis / genetics*
  • Nucleotidyltransferases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • DNA, Neoplasm
  • Membrane Proteins
  • NF-kappa B
  • STING protein, human
  • MB21D1 protein, human
  • Nucleotidyltransferases