Chromosomal Instability Drives Metastasis Through a Cytosolic DNA Response

Overview

Journal Nature

Specialty Science

Date 2018 Jan 18

PMID 29342134

Citations 746

Authors

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 Peer

Don W Cleveland

Simon N Powell

Jan Lammerding

Charles Swanton

Lewis C Cantley

Affiliations

Soon will be listed here.

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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