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 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 and Lewis C. Cantley ()
Additional contact information
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center
Bryan Ngo: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Ashley M. Laughney: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Julie-Ann Cavallo: Memorial Sloan Kettering Cancer Center
Charles J. Murphy: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Peter Ly: Ludwig Institute for Cancer Research, University of California San Diego
Pragya Shah: Nancy E. and Peter C. Meinig School of Biomedical Engineering & Weill Institute for Cell and Molecular Biology, Cornell University
Roshan K. Sriram: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Thomas B. K. Watkins: The Francis Crick Institute
Neil K. Taunk: Memorial Sloan Kettering Cancer Center
Mercedes Duran: Memorial Sloan Kettering Cancer Center
Chantal Pauli: Institute for Pathology and Molecular Pathology, University Hospital Zurich
Christine Shaw: Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center
Kalyani Chadalavada: Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center
Vinagolu K. Rajasekhar: Memorial Sloan Kettering Cancer Center
Giulio Genovese: The Broad Institute of Harvard and MIT, Cambridge
Subramanian Venkatesan: UCL Cancer Institute
Nicolai J. Birkbak: The Francis Crick Institute
Nicholas McGranahan: The Francis Crick Institute
Mark Lundquist: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Quincey LaPlant: Memorial Sloan Kettering Cancer Center
John H. Healey: Memorial Sloan Kettering Cancer Center
Olivier Elemento: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Christine H. Chung: Moffitt Cancer Center
Nancy Y. Lee: Memorial Sloan Kettering Cancer Center
Marcin Imielenski: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Gouri Nanjangud: Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center
Dana Pe’er: Computational Biology Program, Memorial Sloan Kettering Cancer Center
Don W. Cleveland: Ludwig Institute for Cancer Research, University of California San Diego
Simon N. Powell: Memorial Sloan Kettering Cancer Center
Jan Lammerding: Nancy E. and Peter C. Meinig School of Biomedical Engineering & Weill Institute for Cell and Molecular Biology, Cornell University
Charles Swanton: The Francis Crick Institute
Lewis C. Cantley: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine

Nature, 2018, vol. 553, issue 7689, 467-472

Abstract: 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.

Date: 2018
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DOI: 10.1038/nature25432

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