Enzyme that protects against viruses could drive cancer evolution

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Newswise: An enzyme that defends human cells against viruses may help push the evolution of cancer toward greater malignancy by causing myriad mutations in cancer cells, according to a study led by Weill Cornell Medicine researchers. The finding suggests that the enzyme may be a potential target for future cancer treatments.

In the new study, published December 8 in Cancer Research, the scientists used a preclinical model of bladder cancer to investigate the role of the enzyme called APOBEC3G in promoting the disease and found that it significantly increased the number of mutations in the bladder cancer cells. tumor cells, driving the genetic diversity of bladder tumors and accelerating mortality.

“Our findings suggest that APOBEC3G is a major contributor to the progression of bladder cancer and should be considered as a target for future treatment strategies,” said study senior author Bishoy M. Faltas, MD, assistant professor of cell biology. and development at Weill Cornell Medicine. and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center.

The APOBEC3 family of enzymes is capable of mutating RNA or DNA by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in a wrong nucleotide at that position. The normal functions of these enzymes, including APOBEC3G, are to combat retroviruses such as HIV: they attempt to hinder viral replication by mutating cytokines in the viral genome.

The inherent dangerousness of these enzymes suggests that mechanisms must exist to prevent them from damaging cellular DNA. However, about a decade ago, researchers using new DNA sequencing techniques began to find extensive APOBEC3-like mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research at the England Institute of Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a A high proportion of the mutations in these tumors were related to APOBEC3 and that these mutations appeared to play a role in helping the tumors evade the effects of chemotherapy.

Such findings point to the possibility that cancers generally take advantage of APOBEC3s to mutate their genomes. This could help them not only acquire all the mutations necessary for cancerous growth, but also increase their ability to diversify and “evolve” thereafter, allowing further growth and spread despite immune defenses, treatments pharmacological and other adverse factors.

In the new study, Dr. Faltas and his team, including first author Dr. Weisi Liu, a postdoctoral research associate, addressed the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

APOBEC3G is a human enzyme not found in mice, so the team deleted the gene for the only APOBEC3-like enzyme in mice, replacing it with the human APOBEC3G gene. The researchers found that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics carcinogens in cigarette smoke, they became much more likely to develop this form of cancer (76 percent developed cancer) in compared to mice whose APOBEC gene was knocked out. out and not replaced (53% developed cancer). Moreover, during a 30-week observation period, all knockout mice survived, whereas almost a third of the APOBEC3G mice succumbed to cancer.

To their surprise, the researchers found that APOBEC3G in mouse cells was present in the nucleus, where cellular DNA is maintained using a “light section” microscopy technique. Previously, this protein was thought to reside only outside the nucleus. They also found that bladder tumors from APOBEC3G mice had approximately twice as many mutations compared to tumors in knockout-only mice.

By identifying the specific mutational signature of APOBEC3G and mapping it to tumor genomes, the team found ample evidence that the enzyme had caused increased mutational burden and genomic diversity in tumors, likely explaining the increased malignancy and mortality in APOBEC3G mice. . “We saw a distinct mutational signature caused by APOBEC3G in these tumors that is different from the signatures caused by other members of the APOBEC3 family,” Dr. Liu said.

Finally, the researchers searched for the APOBEC3G mutational signature in a widely used human tumor DNA database, The Cancer Genome Atlas, and found that these mutations appear to be common in bladder cancers and are associated with poorer outcomes.

“These findings will inform future efforts to restrict or direct tumor evolution by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with outside organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, consult the profile of Dr. Faltas.

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