Editors' ChoiceCancer

Deadly role of chromosomal instability in metastasis

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Science Translational Medicine  07 Feb 2018:
Vol. 10, Issue 427, eaar7528
DOI: 10.1126/scitranslmed.aar7528


Chromosomal instability produces cytosolic micronuclei that rupture and activate a viral response pathway, driving metastasis.

Metastasis, the spread of cancer cells from the initial tumor site to other organs within the body, is responsible for the majority of cancer-related deaths. One of the hallmarks of cancer is chromosomal instability, wherein an error in chromosomal segregation occurs during cell division, potentially leading to an abnormal number of chromosomes or aneuploidy within cells. There is evidence of increased chromosomal instability in metastatic cancers, but it is a bit of a chicken and egg story—which comes first?

To address the specific role of chromosomal instability in metastasis, Bakhoum, Ngo, and colleagues devised an elegant model system. By overexpressing microtubule depolymerizing proteins (KIF2B or MCAK), they suppressed chromosomal instability within cells that were normally chromosomally unstable but without altering abnormal chromosome numbers or proliferation. Next, they assessed if altered chromosomal stability alone affected the cells’ ability to metastasize. They injected breast cancer cells with stable chromosomes (overexpressing KIF2B or MCAK) into immunocompromised mice and found reduced metastasis and enhanced survival of the mice compared with injection with cells that had unstable chromosomes. They found similar results with lung cancer cells. The authors then tried to identify the mechanism of how chromosomal instability enhanced metastasis. They found increased expression of mesenchymal and inflammatory genes in the chromosomally unstable cells, which also had a greater number of micronuclei in the cytosol. These micronuclei eventually ruptured, releasing DNA into the cytosol and activating the cGAS-STING pathway, an antiviral pathway that senses DNA and activates an inflammatory response. Activation of this pathway is context-dependent, but it can lead to the death of virally infected cells. However, the chromosomally unstable cells do not die but instead undergo enhanced metastasis through noncanonical nuclear factor κB signaling.

Future questions arising from this work include how the antiviral DNA sensing pathway can be targeted to kill chromosomally unstable tumor cells. This study makes an important biological contribution to our understanding of metastasis by uncovering that chromosomally unstable cells have cytosolic micronuclei, which can activate the cCAS-STING antiviral pathway, enhancing metastasis.

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