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; Lewis C. Cantley

doi:10.1038/nature25432

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 LundquistQuincey 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

Research output: Contribution to journal › Article › peer-review

868 Scopus citations

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-? B 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.

Original language	English (US)
Pages (from-to)	467-472
Number of pages	6
Journal	Nature
Volume	553
Issue number	7689
DOIs	https://doi.org/10.1038/nature25432
State	Published - Jan 25 2018
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1038/nature25432

Cite this

Bakhoum, S. F., Ngo, B., Laughney, A. M., Cavallo, J. A., Murphy, C. J., Ly, P., Shah, P., Sriram, R. K., Watkins, T. B. K., Taunk, N. K., Duran, M., Pauli, C., Shaw, C., Chadalavada, K., Rajasekhar, V. K., Genovese, G., Venkatesan, S., Birkbak, N. J., McGranahan, N., ... Cantley, L. C. (2018). Chromosomal instability drives metastasis through a cytosolic DNA response. Nature, 553(7689), 467-472. https://doi.org/10.1038/nature25432

Bakhoum, SF, Ngo, B, Laughney, AM, Cavallo, JA, Murphy, CJ, Ly, P, Shah, P, Sriram, RK, Watkins, TBK, Taunk, NK, Duran, M, Pauli, C, Shaw, C, Chadalavada, K, Rajasekhar, VK, Genovese, G, Venkatesan, S, Birkbak, NJ, McGranahan, N, Lundquist, M, LaPlant, Q, Healey, JH, Elemento, O, Chung, CH, Lee, NY, Imielenski, M, Nanjangud, G, Pe'er, D, Cleveland, DW, Powell, SN, Lammerding, J, Swanton, C & Cantley, LC 2018, 'Chromosomal instability drives metastasis through a cytosolic DNA response', Nature, vol. 553, no. 7689, pp. 467-472. https://doi.org/10.1038/nature25432

@article{c3e1bbb55fa24b65b6bb1f3acea15ee5,

title = "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-? B 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.",

author = "Bakhoum, {Samuel F.} and Bryan Ngo and Laughney, {Ashley M.} and Cavallo, {Julie Ann} and Murphy, {Charles J.} and Peter Ly and Pragya Shah and Sriram, {Roshan K.} and Watkins, {Thomas B.K.} and Taunk, {Neil K.} and Mercedes Duran and Chantal Pauli and Christine Shaw and Kalyani Chadalavada and Rajasekhar, {Vinagolu K.} and Giulio Genovese and Subramanian Venkatesan and Birkbak, {Nicolai J.} and Nicholas McGranahan and Mark Lundquist and Quincey LaPlant and Healey, {John H.} and Olivier Elemento and Chung, {Christine H.} and Lee, {Nancy Y.} and Marcin Imielenski and Gouri Nanjangud and Dana Pe'er and Cleveland, {Don W.} and Powell, {Simon N.} and Jan Lammerding and Charles Swanton and Cantley, {Lewis C.}",

note = "Funding Information: Acknowledgements We thank J. Massagu{\'e}, 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).",

year = "2018",

month = jan,

day = "25",

doi = "10.1038/nature25432",

language = "English (US)",

volume = "553",

pages = "467--472",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7689",

}

TY - JOUR

T1 - Chromosomal instability drives metastasis through a cytosolic DNA response

AU - Bakhoum, Samuel F.

AU - Ngo, Bryan

AU - Laughney, Ashley M.

AU - Cavallo, Julie Ann

AU - Murphy, Charles J.

AU - Ly, Peter

AU - Shah, Pragya

AU - Sriram, Roshan K.

AU - Watkins, Thomas B.K.

AU - Taunk, Neil K.

AU - Duran, Mercedes

AU - Pauli, Chantal

AU - Shaw, Christine

AU - Chadalavada, Kalyani

AU - Rajasekhar, Vinagolu K.

AU - Genovese, Giulio

AU - Venkatesan, Subramanian

AU - Birkbak, Nicolai J.

AU - McGranahan, Nicholas

AU - Lundquist, Mark

AU - LaPlant, Quincey

AU - Healey, John H.

AU - Elemento, Olivier

AU - Chung, Christine H.

AU - Lee, Nancy Y.

AU - Imielenski, Marcin

AU - Nanjangud, Gouri

AU - Pe'er, Dana

AU - Cleveland, Don W.

AU - Powell, Simon N.

AU - Lammerding, Jan

AU - Swanton, Charles

AU - Cantley, Lewis C.

N1 - Funding Information: 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).

PY - 2018/1/25

Y1 - 2018/1/25

N2 - 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-? B 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.

AB - 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-? B 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.

UR - http://www.scopus.com/inward/record.url?scp=85041110925&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041110925&partnerID=8YFLogxK

U2 - 10.1038/nature25432

DO - 10.1038/nature25432

M3 - Article

C2 - 29342134

AN - SCOPUS:85041110925

SN - 0028-0836

VL - 553

SP - 467

EP - 472

JO - Nature

JF - Nature

IS - 7689

ER -

Chromosomal instability drives metastasis through a cytosolic DNA response

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this