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.

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Acknowledgements

We thank J. Massagué, R. Benezra, X. Cai, J. Leeman, M. Bakhoum, B. Hopkins and D. Landau for feedback. Grant support: S.F.B. (DoD Breast Cancer Research Breakthrough Award (BCRBA) W81XWH-16-1-0315, Elsa Pardee Foundation, MSKCC Cytogenetics Core (P30-CA008748) and Core (P30-CA008748) grants); B.N. (NSF Graduate Research Fellowship DGE1257284); J.L. (NIH R01-HL082792, U54-CA210184, DoD BCRBA BC150580, NSF CBET-1254846); P.L. (NCI K99-CA218871); G.G. (DoD BCRBA W81XWH-16-1-0316); L.C.C. (NIH R35-CA197588, U54-CA210184, Breast Cancer Research Foundation, Gray Foundation Basser Initiative).

Author information

Author notes

    • Samuel F. Bakhoum
    •  & Bryan Ngo

    These authors contributed equally to this work.

Affiliations

  1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Samuel F. Bakhoum
    • , Julie-Ann Cavallo
    • , Neil K. Taunk
    • , Mercedes Duran
    • , Quincey LaPlant
    • , Nancy Y. Lee
    •  & Simon N. Powell
  2. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, USA

    • Samuel F. Bakhoum
    • , Bryan Ngo
    • , Julie-Ann Cavallo
    • , Charles J. Murphy
    • , Roshan K. Sriram
    • , Mercedes Duran
    • , Mark Lundquist
    • , Olivier Elemento
    • , Marcin Imielenski
    •  & Lewis C. Cantley
  3. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Ashley M. Laughney
  4. Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California 92093, USA

    • Peter Ly
    •  & Don W. Cleveland
  5. Nancy E. and Peter C. Meinig School of Biomedical Engineering & Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14850, USA

    • Pragya Shah
    •  & Jan Lammerding
  6. The Francis Crick Institute, London NW1 1AT, UK

    • Thomas B. K. Watkins
    • , Nicolai J. Birkbak
    • , Nicholas McGranahan
    •  & Charles Swanton
  7. Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich 8091, Switzerland

    • Chantal Pauli
  8. Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Christine Shaw
    • , Kalyani Chadalavada
    •  & Gouri Nanjangud
  9. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Vinagolu K. Rajasekhar
    •  & John H. Healey
  10. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA

    • Giulio Genovese
  11. UCL Cancer Institute, London WC1E 6BT, UK

    • Subramanian Venkatesan
    • , Nicolai J. Birkbak
    • , Nicholas McGranahan
    •  & Charles Swanton
  12. Moffitt Cancer Center, Tampa, Florida 33612, USA

    • Christine H. Chung
  13. Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Dana Pe’er

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Contributions

S.F.B. and L.C.C. conceived the project; S.F.B., B.N., J.-A.C. and R.K.S. performed animal experiments; V.K.R. derived PDX models; P.L. performed experiments using DLD-1 cells; S.F.B., B.N., J.A.C., R.K.S., M.D., S.V. and Q.L. performed immunostaining, immunoblotting, microscopy and qPCR; P.S. performed live-cell imaging; T.B.K.W., N.J.B. and N.M. analysed matched primary tumour–metastasis data; N.K.T., C.H.C. and S.F.B. analysed the HNSCC data; S.F.B. analysed breast cancer karyotype data; C.P. performed histological analysis; C.S., K.C. and G.N. performed cytogenetic analysis; A.M.L. analysed scRNSseq data; M.L. and S.F.B. analysed survival data; C.J.M. analysed bulk RNAseq data; M.I. analysed whole-genome sequence data; G.G., M.L., Q.L., J.H.H., O.E., C.H.C., N.Y.L., D.P., D.W.C., S.N.P., J.L., C.S. and L.C.C. assisted with data interpretation. All authors contributed to the writing and editing of the manuscript.

Competing interests

L.C.C. owns equity in, receives compensation from, and serves on the board of directors and scientific advisory board of Agios Pharmaceuticals. He is also a founder of and receives laboratory support from Petra Pharmaceuticals. The other authors declare no competing financial interests.

Corresponding author

Correspondence to Lewis C. Cantley.

Reviewer Information Nature thanks N. Gekara, J. van Deursen and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Information

    This file contains Supplementary Tables 1-4 and Supplementary Figures 1-3

Excel files

  1. 1.

    Supplementary Table 5

    This table contains lists of genes belonging to the gene sets mentioned in the study.

  2. 2.

    Supplementary Table 6

    This table contains GSEA results.

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