Ancient Viruses Reawaken To Fuel Modern-Day Cancer Spread

DNA sequences originating from ancient viral infections can play a critical role in helping cancer to survive and thrive.

Long considered inert or “junk DNA”, approximately 8% of the human genome consists of these sequences called endogenous retroviruses (ERVs), which are products of historic viral infections. A new study, published in the journal Science Advances, has now shown that, when reawakened, these sequences can act as “switches” that turn on nearby cancer genes.

“Cancer cells exhibit rewired gene expression, but the underlying mechanisms that cause this have remained elusive,” senior author Dr. Edward Chuong, an assistant professor of molecular, cellular and developmental biology at the University of Colorado Boulder told Technology Networks. “We know that there are disease-specific switches that turn on to cause this, but where do they come from? Our work finds that some of them are derived from ancient viral sequences, which are normally silenced in healthy cells, but become ‘reactivated’ in cancer cells.”

The researchers suggest that silencing certain ERVs could help to improve cancer treatments.

The role of ancient viruses in cancer genomics

ERVs slipped into the cells of human primate ancestors tens of millions of years ago, coaxing their hosts to carry and spread their genetic material.

While they can no longer produce functional viruses, ERVs can function as “switches” that turn on nearby genes. These viruses have played a crucial role in human evolution such as in the development of the placenta as well as in shaping immune responses to modern viruses such as SARS-CoV-2.

“In previous work by us and others, it has been established that ancient viruses can contribute enhancers that have been ‘domesticated’ for beneficial functions, like immunity and development. However, the potential for them to contribute enhancers that have pathological effects has been relatively understudied,” said Chuong. “Yet, we know that diseases like cancer feature genome-wide enhancer dysregulation, which motivated us to look for ERVs that show enhancer activity specifically in cancer cells.”

To explore the role of ERVs in cancer, the researchers analyzed genomic data from 21 human cancer types from publicly available datasets.

They identified LTR10, a specific lineage of ERV that infected primates about 30 million years ago, as showing surprisingly high levels of activity in several types of cancer. Performing bulk and single-cell RNA sequencing analysis of patient tumors revealed that LTR10 elements display tumor-specific transcriptional activation in approximately 30% of cases.

Using CRISPR to silence or knock out sequences where LTR10 was present switched off critical genes known to promote cancer development. When the researchers removed the LTR10 “switch” from mouse tumor cells, key cancer-promoting genes switched off and treatments to shrink tumors were more effective.

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Applications of CRISPR Technology

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The researchers determined that LTR10 appears to switch on genes in the MAP-kinase pathway, a signaling pathway that plays a key role in regulating cellular processes, including cell growth, migration, proliferation, differentiation and survival. This pathway is often adversely rewired in many cancers with MAP-kinase inhibitors used in cancer treatments to block uncontrolled cell division and prevent tumor growth.

These latest findings suggest that treatment with MAPK inhibitors effectively silences LTR10 regulatory activity in cancer cells.

“Many clinical cancer treatments are effective, yet their molecular mechanisms of action remain poorly understood. Understanding these mechanisms would be key to developing more precise therapies with fewer off-target effects on healthy cells,” said Chuong. “Our finding that MAPK inhibitors likely work in part by silencing ERV switches may help clinicians identify optimal MAPK inhibitors based on their activity on these switches.”

Using CRISPR to silence ancient viral DNA

The CRISPR-based epigenome editing technology used in this study to silence ERV switches adjusts gene transcription through the epigenome while leaving the primary DNA sequence intact. This creates possibilities for the potential use of this technology in clinical treatments.

“This same technology is being developed for clinical use, in part because it does not edit the DNA, which always carries the risk of causing more damage like making an oncogenic mutation,” explained Chuong. “Conceivably, this technology could be used to target cancer-specific ERVs like LTR10, which would selectively silence gene expression in cancer cells but would not affect normal cells, where LTR10 elements are already silenced.”

Chuong suspects that ancient viruses could play a role in other diseases where genomic defenses break down and this will be a key area of focus for future studies. He concludes, “Similar studies have been carried out for many other diseases, and we are actively analyzing diseases including aging and autoimmunity, which also see a similar breakdown in the epigenetic defenses seen in healthy cells.”

Dr. Edward Chuong was speaking to Blake Forman, Senior Science Writer for Technology Networks.

About the interviewee:

Dr. Edward Chuong is an assistant professor of molecular, cellular and developmental biology at the University of Colorado Boulder. Chuong received a PhD in genetics from the Stanford University School of Medicine. As a Hanna H. Gray Fellows Program (HHMI) postdoctoral fellow at the University of Utah, Chuong investigated ERVs and their role in the evolution of immune responses. He has been awarded a Packard Fellowship for Science and Engineering (2020) and a Sloan Research Fellowship-Molecular Biology (2019).

Reference: Ivancevic A, Simpson DM, Joyner OM, et al. Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer. Sci Adv. 10, eado1218 (2024). doi: 10.1126/sciadv.ado1218