Peering inside the human genome, among the approximately 20 thousand genes that constitute the building blocks of life, one can also come across fragments of DNA left by viruses that infected our primate ancestors tens of millions of years ago and may be fueling cancer today.
A new study reveals that these bits of ancient viral genome may not be harmless. These ‘hitchhikers’ from the distant past that have traveled with us to the present day, known as endogenous retroviruses, have long been considered inert or ‘junk’ DNA, devoid of any ability to cause harm. But research that casts blame on ‘ancestor viruses’, conducted by a team from the University of Colorado Boulder and published in ‘Science Advances’, shows that, when reawakened, they can play a critical role in helping modern cancers survive and thrive.
But there is also a downside: the study suggests that Silencing some endogenous retroviruses may make cancer treatments work better. The work “highlights that modern diseases may be significantly influenced by these ancient viral infections, which until recently few researchers paid attention to,” notes senior author Edward Chuong, a professor at the University of Michigan’s BioFrontiers Institute. About 8 percent of the human genome is thought to be made up of endogenous retroviruses, the research suggests, that they wormed their way into the cells of our evolutionary ancestors, tricking their hosts into copying and carrying their genetic material. Over time, they infiltrated sperm, eggs, and embryos, baking their DNA like a fossil record for generations to come, shaping evolution along the way.
Even though they can no longer produce functional viruses, Research has shown that endogenous retroviruses can act as ‘switches’ that activate nearby genes. Some have contributed to the development of the placenta, a milestone in human evolution, and to the immune response to modern viruses like Covid. “There have been studies that show that these endogenous retroviruses can be domesticated to our advantage, but there aren’t many that show how they could harm us,” Chuong says.
To explore their role in cancer, he and his lab’s first author Atma Ivancevic analyzed genomic data from publicly available datasets for 21 human cancers. They found that a specific lineage of endogenous retrovirus known as LTR10, which infected primates about 30 million years ago, showed surprisingly high levels of activity in several cancers, including lung and colon. Further analysis of tumors from dozens of colorectal cancer patients revealed that LTR10 was active in about a third of the cases.
When the team used the gene-editing tool Crispr to cut out or silence the sequences where it was present, they found that critical genes known to promote cancer development and growth were also inactive.
“We saw that when you silence this retrovirus in tumor cells, you turn off the expression of genes nearby.”Ivancevic reports. Experiments in mice produced similar results: When an LTR10 switch was removed from tumor cells, key cancer-promoting genes, including one called XRCC4, also turned off, and treatments to shrink tumors worked better.
“We know that cancer cells express a lot of genes that shouldn’t be turned on, but no one really knows what turns them on,” Chuong says. And now it turns out that “a lot of the switches that turn them on come from these ancient viruses.” In particular, the endogenous retrovirus studied appears to turn on genes in a well-known cellular pathway, the MAP kinase pathway, which is negatively reprogrammed in many cancers. MAP kinase-inhibiting drugs likely work, in part, by turning off the endogenous retrovirus, the study suggests.
The authors note that this family of retroviruses alone regulates up to 70 genes associated with cancer in this pathway. Different lineages likely influence different pathways that promote different cancers. Chuong suspects that as people age, their genomic defenses deteriorate, allowing ancient viruses to reawaken and contribute to other health problems as well. “The origins of how disease manifests in the cell have always been a mystery,” Chuong says. “Endogenous retroviruses aren’t the whole story, but they could be an important part of it.”
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