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Chromosomal instability drives metastasis through a cytosolic DNA response
- Bakhoum, Samuel F;
- Ngo, Bryan;
- Laughney, Ashley M;
- Cavallo, Julie-Ann;
- Murphy, Charles J;
- Ly, Peter;
- Shah, Pragya;
- Sriram, Roshan K;
- Watkins, Thomas BK;
- Taunk, Neil K;
- Duran, Mercedes;
- Pauli, Chantal;
- Shaw, Christine;
- Chadalavada, Kalyani;
- Rajasekhar, Vinagolu K;
- Genovese, Giulio;
- Venkatesan, Subramanian;
- Birkbak, Nicolai J;
- McGranahan, Nicholas;
- Lundquist, Mark;
- LaPlant, Quincey;
- Healey, John H;
- Elemento, Olivier;
- Chung, Christine H;
- Lee, Nancy Y;
- Imielenski, Marcin;
- Nanjangud, Gouri;
- Pe’er, Dana;
- Cleveland, Don W;
- Powell, Simon N;
- Lammerding, Jan;
- Swanton, Charles;
- Cantley, Lewis C
- et al.
Published Web Location
https://doi.org/10.1038/nature25432Abstract
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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