Chromosomal instability drives metastasis through a cytosolic DNA response

By S. Bakhoum, B. Ngo, Ashley M. Laughney, J. Cavallo, C. Murphy, P. Ly, Pragya Shah, Roshan K. Sriram, T. Watkins, Neil K. Taunk and 23 more. Nature, 2018

1,367 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3b57dcc28a01c5a66fdf7910ccfc6bc02b5b93bb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. A. Ablasser
2. Zhijian J. Chen
3. Shizuo Akira
4. N. Perkins
5. Tuo Li
6. G. Barber
7. Ivan Dikic
8. Taro Kawai

In Molecular Biology

1. A. Ablasser
2. Zhijian J. Chen
3. Raghu Kalluri
4. M. Nieto
5. R. Weinberg
6. D. Hanahan
7. Zena Werb
8. Youhua Liu

Citations in the corpus

• cGAS in action: Expanding roles in immunity and inflammation (2019, background): “In addition, cGAS-STING signaling has been shown to activate canonical and—in cancer cells— noncanonical nuclear factor kB (NF-kB),mitogenactivated protein (MAP) kinases, and signal transducer and activator of transcription (STAT) transcription factors (28, 29).”
• Systems Biology of Cancer Metastasis (2019, background): “Cancer cells are capable of morphologically adapting to the physical constraints of the microenvironment, including deformation of the rigid nucleus, which, in turn, can lead to chromosomal instability, altered gene expression, and metastasis(Bakhoum et al., 2018).”