Surprising: An ancient virus hidden in the human genome provides a new target fo

Posted by Jerry Carter on June 1st, 2021

In the human genome, about 8% of the DNA is the remnants of retroviruses that infect humans or human ancestors in ancient times, which have become part of the human genome. Some of these sequences can even be traced back to hundreds of millions of years ago.

Previous studies have shown that some of these ancient retroviruses (also known as endogenous retroviruses, or ERVs for short) play a role in cancer. Although ERV sequences will fall asleep over time and cannot produce virus particles, sometimes they are inserted into other genes to disrupt their normal activities or act as switches for oncogenes. However, recent studies show that if ERVs are transcribed into RNA strands, they may also play an anti-cancer effect. When a large number of originally sleeping ERVs are activated, they will produce a large amount of double-stranded RNA and enter the cytoplasm, thereby forming virus infection-like state to ignite inflammatory response. In this way, ERV may make cancer more sensitive to immunotherapy.

On May 10, 2021, the Adam Bass team of the Dana-Farber Institute of Harvard Medical School published a research paper titled Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence in Nature Genetics.

The study found that the oncogene SOX2 in esophageal cancer activates the expression of ancient retroviruses embedded in the human genome, thereby prompting esophageal cancer cells to become dependent on ADAR1. These findings reveal the new weakness of esophageal cancer with SOX2 overexpression. Blocking ADAR1 is likely to have a direct curative effect, which may also play a greater value by improving the effectiveness of cancer immunotherapy on patients with esophageal cancer.

According to the latest global cancer burden data released by the International Agency for Research on Cancer (IARC) in 2020, esophageal cancer is the eighth number of new malignancies in the world and the sixth number of deaths.

In this study, the research team created esophageal organoids from mouse tissues to track the progression of cancer from normal cells to malignant tumors. It was found that a specific oncogene SOX2 in esophageal cancer can induce the expression of many ERVs. The accumulation of double-stranded RNAs caused by the expression of ERV may have a toxic effect on cells. The research team further discovered that the ADAR1 enzyme (a double-strand specific RNA editing enzyme) can quickly degrade these double-stranded RNAs.

According to previous studies, ADAR1 level is associated with poor prognosis of esophageal cancer. This study shows that cancers rely on ADAR1 to prevent immune responses that may be very toxic to cells.

Cancer immunotherapy represented by PD-1/PD-L1 inhibitors has already been applied to the treatment of esophageal cancer, which can prolong the survival period of patients by several months.

In view of the above findings, blocking ADAR1 is likely to have a direct effect on esophageal cancer, which may also improve the effect of cancer immunotherapy.

Organoids—explore targets of cancer treatment

Using organoids to generate cancer from normal cells is a powerful method to reveal cancer-causing activities and test therapeutic targets. By making individual gene changes in these organoid models, it is intuitive to find out which combinations of gene changes cause cancer, thereby helping to determine the specific mechanism of tumor formation.

In this study, the research team established an esophageal organoid to simulate and track cancer development, which starts from the overexpression of SOX2 gene, one of the gene characteristics of esophageal cancer. The research team analyzed the difference in the activity of SOX2 in normal tissues and cancerous tissues. Study on organoids with both SOX2 overexpression and tumor suppressor gene p53/p16 deletions found that SOX2 will turn on the expression of various oncogenes and activate the endogenous retroviruses (ERVs), making cancer cells more dependent on ADAR1.

Since SOX2 also exists and functions in normal esophageal cells, it cannot be directly used as a therapeutic target. However, the findings reveal that blocking ADAR1 is likely to have a direct effect on esophageal cancer, which may also improve the effect of cancer immunotherapy.