Chromosomal instability drives metastasis through a cytosolic DNA response

被引：1230

作者：

Bakhoum, Samuel F. ^{[1
,2
]}

Ngo, Bryan ^{[2
]}

Laughney, Ashley M. ^{[3
]}

Cavallo, Julie-Ann ^{[1
,2
]}

Murphy, Charles J. ^{[2
]}

Ly, Peter ^{[4
]}

Shah, Pragya ^{[5
,6
]}

Sriram, Roshan K. ^{[2
]}

Watkins, Thomas B. K. ^{[7
]}

Taunk, Neil K. ^{[1
]}

Duran, Mercedes ^{[1
,2
]}

Pauli, Chantal ^{[8
]}

Shaw, Christine ^{[9
]}

Chadalavada, Kalyani ^{[9
]}

Rajasekhar, Vinagolu K. ^{[10
]}

Genovese, Giulio ^{[11
]}

Venkatesan, Subramanian ^{[12
]}

Birkbak, Nicolai J. ^{[7
,12
]}

McGranahan, Nicholas ^{[7
,12
]}

Lundquist, Mark ^{[2
]}

LaPlant, Quincey ^{[1
]}

Healey, John H. ^{[10
]}

Elemento, Olivier ^{[2
]}

Chung, Christine H. ^{[13
]}

Lee, Nancy Y. ^{[1
]}

Imielenski, Marcin ^{[2
]}

Nanjangud, Gouri ^{[9
]}

Pe'er, Dana ^{[14
]}

Cleveland, Don W. ^{[4
]}

Powell, Simon N. ^{[1
]}

Lammerding, Jan ^{[5
,6
]}

Swanton, Charles ^{[7
,12
]}

Cantley, Lewis C. ^{[2
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA

[2] Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[4] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[5] Cornell Univ, Nancy E & Peter C Meinig Sch Biomed Engn, Ithaca, NY 14850 USA

[6] Cornell Univ, Weill Inst Cell & Mol Biol, Ithaca, NY 14850 USA

[7] Francis Crick Inst, London NW1 1AT, England

[8] Univ Hosp Zurich, Inst Pathol & Mol Pathol, CH-8091 Zurich, Switzerland

[9] Mem Sloan Kettering Canc Ctr, Mol Cytogenet Core, New York, NY 10065 USA

[10] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[11] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[12] UCL Canc Inst, London WC1E 6BT, England

[13] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA

[14] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA

来源：

NATURE | 2018年 / 553卷 / 7689期

基金：

美国国家科学基金会;

关键词：

BREAST-CANCER; ANEUPLOIDY; CELLS; SENSITIVITY; PROGNOSIS; EVOLUTION; CGAS; TOOL;

D O I：

10.1038/nature25432

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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-kappa 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.

引用

页码：467 / +

页数：30

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