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.

• Authors: 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 Lundquist, Quincey 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
• Journal: Nature (Nature) Vol. 553 Issue 7689 Pg. 467-472 (01 25 2018) ISSN: 1476-4687 [Electronic] England
• PMID: 29342134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA, Neoplasm
• Membrane Proteins
• NF-kappa B
• STING1 protein, human
• Nucleotidyltransferases
• cGAS protein, human

Topics

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