Chronic leakage of DNA within tumor cells may be at the root of metastasis in approximately 50% of cancers, according to researchers at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSKCC). In a study recently published in Nature, the researchers trace a complex chain of events that starts with chromosomal instability leading to metastatic disease.
Lead author Samuel Bakhoum, MD, a research fellow at Weill Cornell Medicine and senior resident in radiation oncology at MSKCC in New York, New York, said a leakage of DNA from the nuclei of cancer cells leads to a chronic inflammatory response within the cells. The researchers injected chromosomally unstable tumor cells into mice and found that they were significantly more likely to spread and form new tumors compared with tumor cells in which chromosomal instability was suppressed. That was true even though both sets of tumor cells started out genetically identical.
The researchers examined gene activity in these two sets of tumor cells and found that those with high chromosomal instability had abnormally elevated activity stemming from more than 1,500 genes. Many of the genes with elevated activity were found to be specifically involved in inflammation and the response of the immune system to viral infections.
“This work makes an unexpected discovery linking a form of genetic instability called chromosomal instability to cancer metastasis through chronic inflammation. It is also the first in identifying a widespread genomic driver of metastasis,” Dr. Bakhoum told Cancer Network.
He said these findings may explain why focusing on individual cancer mutations have not yielded clear drivers of metastasis. The current study suggests that chromosomal instability appears to promote aggressive cancer cell behavior by sustaining a chronic inflammatory response to the leakage of genomic DNA. “This DNA leak is reminiscent of an infection by a virus and it leads to the activation of the cGAS-STING cytosolic DNA-sensing innate immune pathway,” said Dr. Bakhoum.
The researchers found that lowering cGAS-STING levels reduced inflammation and prevented the ability of otherwise aggressive tumor cells to metastasize when injected into mice. If further studies validate these initial findings, then chromosomal instability could serve as an important prognostic marker for risk stratification as well as a predictive marker for therapeutic resistance.
The current findings also suggest caution with respect to a new class of treatments that aim to activate the cGAS-STING pathway in tumors. Dr. Bakhoum said these are sometimes referred to as STING agonists and while engaging the cGAS-STING cytosolic DNA sensing pathway has been shown to activate the immune system, it might also have a dark side. He said STING agonists could fuel cancer cells to become more aggressive and facilitate tumor spread.
He said there are at least two potential therapeutic strategies now worth considering. The first is to pharmacologically suppress chromosomal instability in early-stage cancers, and the second would is to identify ways to restore normal responses to inflammation and cytosolic DNA.