Esophageal cancer turns on ancient viral DNA hidden in our genome

Scientists have discovered that many esophageal cancers turn on ancient viral DNA that was embedded in our genome hundreds of millions of years ago.

“It was amazing,” said Adam Bath, MD, professor of Herbert and Florence Irving Medicine at Columbia University’s Bageros Medical Surgery University, who led the study published May 10. I will. Nature genetics..

“We weren’t looking for a viral component in particular, but this discovery opens up a huge new sequence of potential cancer targets that I find very exciting as a way to enhance immunotherapy.”

Fossil virus and cancer

The idea that an endogenous retrovirus element, or a fragment of an ancient retrovirus in the human genome known as the ERV, plays a role in cancer is not new. The ERV sequence is degraded over time and unable to produce viral particles, but viral fossils can be inserted into other genes, which can disrupt normal activity or turn on genes that cause cancer. It also functions as a switch.

However, recent studies suggest that ERV may also fight cancer if it is transcribed into RNA strands.

When a cell activates many ERVs, many double-stranded RNAs are produced and enter the cytoplasm of the cell. It creates a condition like a viral infection and can cause an inflammatory response. Thus, ERV can make cancer more susceptible to immunotherapy, and many researchers are working on ways to trick cancer cells into activating ERV. “

Dr. Adam Bath, Professor of Herbert and Florence Irving Medicine, Columbia University Bageros Medical College and Herbert Irving Cancer Center

Esophageal cancer turns on ERV

In a new study, Bass and his colleagues created esophageal organoids from mouse tissue to track the development of cancer from normal cells to malignant tumors.

Using these organoids, Bass discovered that a specific cancer-promoting gene for esophageal cancer called SOX2 leads to the induction of the expression of many ERVs.

Because ERV expression and the accumulation of double-stranded RNA resulting from ERV expression can be toxic to cells, researchers have found a specific enzyme called ADAR1 that rapidly degrades these double-stranded RNAs. I found that there is.

Its role is unknown, but ADAR1 has been implicated in esophageal cancer by other researchers. ADAR1 levels are known to correlate with reduced survival. “Cancer relies on ADAR1 to prevent an immune response that can be very toxic to cells,” says Bass.

Some patients with esophageal cancer are currently being treated with immunotherapy. Immunotherapy has been shown to prolong survival by several months. “There is enthusiasm that blocking ADAR1 may have a direct effect on esophageal cancer, and that strengthening ADAR1 inhibition may have even greater effects. Effectiveness of Cancer immunotherapy for patients with esophageal cancer. “

Organoids reveal other potential targets for SOX2 cancer

In addition to the results for ADAR1 and ERV, the process of modeling the development of esophageal cancer through organoid genomic engineering has also revealed many other processes of esophageal cancer that may lead to new therapies.

“The method of using organoids to build cancer from normal cells is a powerful system for identifying the activities that cause cancer and testing therapeutic targets,” says Bass. “By making individual genomic changes one at a time in these models, we can identify which combination of genetic changes leads to cancer and determine specific mechanisms of tumorigenesis.”

Organoids in current studies began with overexpression of the SOX2 gene, a commonly amplified factor that promotes the development of squamous cell carcinoma.

In this study, the Bass team built a panel of organoids that model the spectrum from the normal esophagus to fully transformed cancer.

By being able to assess the different characteristics of normal and cancerous organoids, the team was able to analyze how SOX2 activity differs between normal and cancerous tissues. “Potential treatments need to target the function of the cancer, but it has little effect on normal tissue, so it’s important to understand the difference,” he says. “Killing cancer cells is relatively easy. The question is how to kill cancer cells but spare other cells.”

Organoids, when SOX2 is overactivated and two tumor suppressors are inactivated, SOX2 works with other factors to produce various cancer-causing genes in addition to their effects on ERV induction. I made it clear that I would turn it on.

“These findings reveal new vulnerabilities in SOX2 esophageal cancer that allow us to begin developing treatments that can accurately target cancer cells and improve patient treatment. “I will,” said Mr. Bass.