[Nature Magazine] Harvard scientists are exploring the mystery of esophageal cancer and ancient viruses. Blocking the ADAR1 enzyme is so important!

This article is original by Translational Medicine.
Please indicate the source for reprinting.
Author: Catalina Introduction: Harvard scientists found that overexpression of the oncogene SOX2 activates ancient retroviruses and makes cancer cells more dependent on the ADAR1 enzyme by establishing a brand-new esophageal organoid.

Blocking ADAR1 may have a direct effect on the treatment of esophageal cancer.

Esophageal cancer is a malignant tumor that occurs in the epithelial tissue of the esophagus.

China is an area with a high incidence of esophageal cancer.
Smoking and drinking are common causes of esophageal cancer, of which esophageal squamous cell carcinoma (ESCC) is the most common.

As early as 2009, Professor Adam Bass of Harvard Medical School's Dana-Farber Cancer Institute determined that repeated amplification of chromosome 3q targeting the transcription factor SOX2 is an important reason for the existence of ESCC.

On May 10, 2021, Professor Adam Bass and his team made a new breakthrough in ESCC and published the paper in "Nature Genetics" entitled "Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence".

The study established a new set of esophageal organoids to show that when the oncogene SOX2 is overactive, it can induce the expression of ancient transcription viruses, thereby making esophageal cancer dependent on the ADAR1 enzyme, providing a new target for cancer treatment.

In this study, the Bass team established a set of esophageal organoid models to simulate and track the development of cancer from normal esophagus to fully transformed, and mapped the epigenetic and transcriptional maps of the SOX2 gene.

The organoids under current research begin with the overexpression of SOX2 gene, which is a common amplification factor that promotes the development of squamous carcinoma.

Ancient viruses and cancer Some ancient retroviruses (called endogenous retroviral elements, or ERV) in the human genome play a role in cancer.

Although the ERV sequence has degenerated over time and cannot produce virus particles, it sometimes inserts other genes to disrupt normal activities or act as a switch for oncogenes.

However, recent studies have shown that when ERV is transcribed into RNA strands, they can also fight cancer.

When cells activate a large amount of ERV, a large amount of double-stranded RNA is produced and enters the cytoplasm, which creates a state similar to a virus infection and may lead to an inflammatory response in the body.

Later, ERV may make cancer more susceptible to immunotherapy.
Therefore, many researchers are studying ways to induce cancer cells to activate ERV.

Esophageal cancer turns on ERV.
In this new study, researchers created esophageal organoids from mouse tissues to track the progression of cancer from normal cells to malignant tumors.

Using these organoids, they found that a specific oncogene SOX2 in esophageal cancer can induce the expression of many ERVs.

The expression of ERV and the accumulation of double-stranded RNA are toxic to cells.
Researchers have discovered that an enzyme called ADAR1 can quickly degrade these double-stranded RNAs.

Previous studies have shown that ADAR1 is associated with esophageal cancer, and ADAR1 levels are associated with low survival rates.

Cancer depends on ADAR1 to prevent immune response, which is very harmful to cells.

Some patients with esophageal cancer treated with immunotherapy have proven that this can increase survival rates for several months.

Blocking ADAR1 may have a direct effect on esophageal cancer, and inhibiting ADAR1 may have a huge effect by enhancing the efficacy of cancer immunotherapy in patients with esophageal cancer.

Organoids reveal SOX2 carcinogenic targets In addition to the results of ADAR1 and ERV, the simulation of esophageal cancer organoids also reveals other processes of esophageal cancer.

In this study, the team analyzed the difference in activity of SOX2 in normal and cancerous tissues.

These organoids reveal that when SOX2 is overactive, SOX2 will turn on the expression of various oncogenes, and it will also activate ancient retroviruses (ERV), making cancer cells more dependent on ADAR1.

Since SOX2 also exists and plays an important role in normal esophageal cells, it cannot be directly used as a therapeutic target.
However, these findings reveal new weaknesses in SOX2 overexpression in esophageal cancer.
Blocking ADAR1 is likely to have a direct effect on esophageal cancer.
Moreover, It is also possible to improve the effect of cancer immunotherapy on patients with esophageal cancer and exert greater value.

In short, SOX2 regulates the epigenetics of esophageal cancer, and finally locks the ADAR1 enzyme as a new target for esophageal cancer.

Reference materials: Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options.

If you need health guidance, please go to a regular hospital for treatment.