A new landmark study published by a research team has disclosed that ancient viruses buried inside our DNA are very active in the proliferation of modern human cancers. Targeting viral remnants could lead to the development of more effective treatments against deadly diseases.
“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 Edward Chuong, an assistant professor of molecular, cellular, and developmental biology at CU Boulder.
Some 8% of the human genome is composed of endogenous retroviruses, viral elements that are integrated into the cells of our evolutionary ancestors. Over time, these retroviruses infected sperm, eggs, and embryos and left their DNA behind, an almost fossil record that helped drive evolution. Though they now can’t replicate into functional viruses, studies from Chuong’s lab have shown that endogenous retroviruses can act as “switches” to turn on the activity of adjacent genes. Some have been co-opted for placentation and immune defense against modern viruses, like COVID-19.
According to a new study in the journal Science Advances, these ancient hitchhikers can help cancer survive and thrive when they are re-awakened. The researchers also showed that silencing certain endogenous retroviruses might make cancer treatments more effective.
Chuong and his colleagues ran genomic analyses across 21 human cancer types, and they found that a specific endogenous retrovirus lineage called LTR10, which had originally infected some primates around 30 million years ago, was highly expressed in some different cancers, including lung and colon cancer. Deeper analysis of the tumors from colorectal cancer patients showed that about one-third of those tumors had active LTR10.
The researchers, utilizing the gene-editing tool CRISPR, have found out that LTR10 sequences turn off many key genes that are known to promote the development and growth of cancer. Similar experiments in mice demonstrated that when an LTR10 “switch” is removed from tumor cells, important genes promoting cancer, including one called XRCC4, switch off, too; treatments against shrinking tumors work more effectively.
“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,” Chuong said. “It turns out many of the switches turning them on are derived from these ancient viruses.”
It appears that this endogenous retrovirus studied can turn on genes in the MAP-kinase pathway, a cellular pathway that goes awry in many cancers. Existing drugs known as MAP-kinase inhibitors likely work, in part, by disabling the endogenous retrovirus switch.
Chuong suspects that as people age, their genomic defenses break down, enabling 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,” he said. “Endogenous retroviruses are not the whole story, but they could be a big part of it.”
The work thus opens up fresh avenues in understanding the underlying complex mechanisms of cancer and perhaps other diseases, too, through the revelation of hidden viral elements that take an active part in sculpting our health to this very day.