Peek inside the human genome and, among the 20,000 or so genes that serve as building blocks of life, you'll also find flecks of DNA left behind by viruses that infected primate ancestors tens of millions of years ago.
These ancient hitchhikers, known as endogenous retroviruses, were long considered inert or "junk" DNA, defanged of any ability to do damage. New CU Boulder research published July 17 in the journal "Science Advances" shows that, when reawakened, they can play a critical role in helping cancer survive and thrive. The study also suggests that silencing certain endogenous retroviruses can make cancer treatments work better.
"Our study shows that diseases today can be significantly influenced by these ancient viral infections that until recently very few researchers were paying attention to," said senior author Edward Chuong, an assistant professor of molecular, cellular and developmental biology at CU Boulder's BioFrontiers Institute.
Studies show about 8% of the human genome is made up of endogenous retroviruses that slipped into the cells of our evolutionary ancestors, coaxing their hosts to copy and carry their genetic material. Over time, they infiltrated sperm, eggs and embryos, baking their DNA like a fossil record into generations to come-and shaping evolution along the way.
Edward Chuong (Credit: Glenn Asakawa/CU Boulder)
Even though they can no longer produce functional viruses, Chuong's own research has shown that endogenous retroviruses can act as "switches" that turn on nearby genes. Some have contributed to the development of the placenta, a critical milestone in human evolution, as well as our immune response to modern-day viruses like COVID.
"There's been a lot of work showing these endogenous retroviruses can be domesticated for our benefit, but not a lot showing how they might hurt us," he said.
Switching cancer genes on
To explore their role in cancer, Chuong and first author Atma Ivancevic, a research associate in his lab, analyzed genomic data from 21 human cancer types from publicly available datasets.
They found that a specific lineage of endogenous retrovirus known as LTR10, which infected some primates about 30 million years ago, showed surprisingly high levels of activity in several types of cancer, including lung and colon cancer. Further analysis of tumors from dozens of colorectal cancer patients revealed that LTR10 was active in about a third of them.
When the team used the CRISPR gene editing tool to snip out or silence sequences where it was present, they discovered that critical genes known to promote cancer development and growth also went dark.
"We saw that when you silence this retrovirus in cancer cells, it turns off nearby gene expression," said Ivancevic.
Experiments in mice yielded similar results: When an LTR10 "switch" was removed from tumor cells, key cancer-promoting genes, including one called XRCC4, switched off too, and treatments to shrink tumors worked better.
"We know that cancer cells express a lot of genes that are not supposed to be on, but no one really knows what is turning them on," said Chuong. "It turns out many of the switches turning them on are derived from these ancient viruses."
Notably, the endogenous retrovirus they studied appears to switch on genes in what is known as the MAP-kinase pathway, a famed cellular pathway that is adversely rewired in many cancers. Existing blockbuster drugs on the market, known as MAP-kinase inhibitors, likely work, in part, by disabling the endogenous retrovirus switch, the study suggests.
Reawakening ancient viruses
The authors note that just this one family of retrovirus regulates as many as 70 cancer-associated genes in this pathway. Different lineages likely influence different pathways that promote different cancers.
The team plans to look into some of them next.
"Any time we can find out how genes or pathways that are inherently altered in tumors are regulated, that is really helpful," said co-author Todd Pitts, associate professor of medical oncology with the CU Cancer Center. "It allows us to potentially find new therapies or find patients that might respond better to current therapies."
The study is not the first to implicate ancient viruses in cancer. Previous studies suggest they may emit toxic compounds or spark genetic mutations. And two other recent studies show that they switch on cellular pathways in leukemia and prostate cancer.
Chuong said that while these shadow viruses are likely an underappreciated source of genetic influence across all cancer types, this study doesn't show they cause cancer. Rather, cancer itself wakes them up, empowering them to activate other disease-promoting processes to help keep it alive.
He suspects that as people's cells age, their genomic defenses break down, enabling other ancient viruses to reawaken and contribute to other health problems too.
"The origins of how diseases manifest themselves in the cell have always been a mystery," said Chuong. "Endogenous retroviruses are not the whole story, but they could be a big part of it."
