Menu

Chromosomal Instability Drives Cancer Metastasis

In the presence of cytosolic DNA, cancer cells activate antiviral pathways that disguise them as immune cells.

Apr 1, 2018
Jim Daley

BREAKING FREE: When a chromosomally unstable cell divides, its chromosomes can become disordered during anaphase (1). Errors in segregation can allow chromosomes to leak into the cytosol, where they form “micronuclei” (2), which trigger an inflammatory response in the daughter cell (3). This response can lead to metastasis.
See full infographic: WEB
© IKUMI KAYAMA/STUDIO KAYAMA

 

EDITOR'S CHOICE IN ONCOLOGY

The paper
S.F. Bakhoum et al., “Chromosomal instability drives metastasis through a cytosolic DNA response,” Nature, 553:467-72, 2018.

Aneuploidy—the presence of abnormal numbers of chromosomes in a cell—is associated with cancer metastasis, but scientists have struggled to connect the mechanistic dots underlying the phenomenon. To explore the association, a team of researchers led by Lewis Cantley, a cancer biologist at Weill Cornell Medicine, and Sam Bakhoum, a radiation oncologist at Memorial Sloan Kettering Cancer Center, recently injected chromosomally unstable breast and lung cancer cells into mice, and saw that the cells were more likely to metastasize than cells in which chromosomal instability was suppressed. To the researchers’ surprise, they also observed a heightened inflammatory response in the chromosomally unstable cells even before they were injected into the mice.

These findings led the scientists to examine whether the cells had an innate immune response to cytosolic DNA. Ongoing segregation errors in cancer cells can allow chromosomes to leak from the nucleus into the cytosol, forming “micronuclei” that expose naked DNA to the cytosol when they rupture. The research team first compared genomic integrity—a proxy for chromosomal stability—of primary tumors and metastases in data from a 2015 study, and found more instability in the metastases. They then transplanted metastatic cancer cells with chromosomal instability into mice, and found that an antiviral immune response called the cGAS-STING pathway was chronically switched on in the cells.

Normally, epithelial cells immediately die when cGAS-STING signals are expressed. But Bakhoum says metastatic cancer cells may adapt not just to survive the activation, but to use it to their advantage. That’s because the same cytosolic DNA–activated pathway mediates the migration of macrophages and other immune cells to an area apparently under viral attack. This raises the possibility that cancer cells are “reacting to cytosolic DNA like immune cells rather than like normal epithelial cells,” he says, enabling them to metastasize to distant sites.

“The analogy I like to use is [a] wolf in sheep’s clothing,” adds Cantley. Testing for cytosolic DNA in a primary tumor could “be predictive of who’s going to metastasize,” he says.

Virginia Tech cell biologist Daniela Cimini, who has collaborated with Bakhoum in the past but was not involved in this study, says it raises a red flag for one therapeutic avenue. “A lot of labs right now are focusing on possibly increasing chromosomal instability as a therapeutic strategy for cancer,” because such instability appears to disrupt tumor formation and early progression, Cimini tells The Scientist. “If [chromosomal instability] promotes metastasis, now we’re in trouble.”

Cantley says the study may also have implications for the use of current treatments, such as radiation and chemotherapy, that also induce chromosomal instability. “We . . . have to be cognizant of the possibility that many of our therapies for primary tumors are probably actually increasing the probability of metastasis.”

January 2019

Cannabis on Board

Research suggests ill effects of cannabinoids in the womb

Marketplace

Sponsored Product Updates

WIN a VIAFLO 96/384 to supercharge your microplate pipetting!
WIN a VIAFLO 96/384 to supercharge your microplate pipetting!
INTEGRA Biosciences is offering labs the chance to win a VIAFLO 96/384 pipette. Designed to simplify plate replication, plate reformatting or reservoir-to-plate transfers, the VIAFLO 96/384 allows labs without the space or budget for an expensive pipetting robot to increase the speed and throughput of routine tasks.
FORMULATRIX® digital PCR technology to be acquired by QIAGEN
FORMULATRIX® digital PCR technology to be acquired by QIAGEN
FORMULATRIX has announced that their digital PCR assets, including the CONSTELLATION® series of instruments, is being acquired by QIAGEN N.V. (NYSE: QGEN, Frankfurt Stock Exchange: QIA) for up to $260 million ($125 million upfront payment and $135 million of milestones).  QIAGEN has announced plans for a global launch in 2020 of a new series of digital PCR platforms that utilize the advanced dPCR technology developed by FORMULATRIX combined with QIAGEN’s expertise in assay development and automation.
Application of CRISPR/Cas to the Generation of Genetically Engineered Mice
Application of CRISPR/Cas to the Generation of Genetically Engineered Mice
With this application note from Taconic, learn about the power that the CRISPR/Cas system has to revolutionize the field of custom mouse model generation!
Translational Models of Obesity, Dysmetabolism, Diabetes, and Complications
Translational Models of Obesity, Dysmetabolism, Diabetes, and Complications
This webinar, from Crown Bioscience, presents a unique continuum of translational dysmetabolic platforms that more closely mimic human disease. Learn about using next-generation rodent and spontaneously diabetic non-human primate models to accurately model human-relevant disease progression and complications related to obesity and diabetes here!