Weill Cornell Medicine / Lewis C. Cantley*
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.
Bakhoum SF1,2, Ngo B2, Laughney AM3, Cavallo JA1,2, Murphy CJ2, Ly P4, Shah P5, Sriram RK2, Watkins TBK6, Taunk NK1, Duran M1,2, Pauli C7, Shaw C8, Chadalavada K8, Rajasekhar VK9, Genovese G10, Venkatesan S11, Birkbak NJ6,11, McGranahan N6,11, Lundquist M2, LaPlant Q1, Healey JH9, Elemento O2, Chung CH12, Lee NY1, Imielenski M2, Nanjangud G8, Pe'er D13, Cleveland DW4, Powell SN1, Lammerding J5, Swanton C6,11, Cantley LC2.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, USA.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California 92093, USA.
Nancy E. and Peter C. Meinig School of Biomedical Engineering & Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14850, USA.
The Francis Crick Institute, London NW1 1AT, UK.
Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
UCL Cancer Institute, London WC1E 6BT, UK.
Moffitt Cancer Center, Tampa, Florida 33612, USA.
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.