Endogenous retroviral elements (ERVs)—the ancient viral DNA sequences that lurk in our genome—have lost the ability to produce viral particles, but they can still cause mischief. For example, they can take part in the tangled mechanisms that give rise to cancer. However, in esophageal cancers associated with a cancer-promoting gene called SOX2, ERVs could make cancer cells more vulnerable to immunotherapy.
This possibility was recognized in a recent study led by Adam Bass, MD, a researcher at Columbia University. In this study, Bass and his colleagues created esophageal organoids from mouse tissue to follow the development of cancer from normal cells to malignancy. Using these organoids, the scientists found that a specific cancer-promoting gene in esophageal cancers called SOX2 leads to induction of expression of many ERVs.
“When cells activate lots of ERVs, a lot of double-stranded RNA is made and gets into the cell cytoplasm,” Bass said. “That creates a state that’s like a viral infection and can cause an inflammatory response. In that way, ERVs may make the cancer more susceptible to immunotherapy, and many researchers are working on ways to trick cancer cells into activating ERVs.”
“It was surprising,” Bass continued. “We weren’t specifically searching for the viral elements, but the finding opens up a huge new array of potential cancer targets that I think will be extremely exciting as ways to enhance immunotherapy.”
Details of the work appeared May 10 in the journal Nature Medicine, in an article titled, “Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence.” ADAR1, an RNA-editing enzyme, quickly degrades the double-stranded RNAs expressed from activated ERVs.
If not for ADAR1, esophageal cancer cells would accumulate so many double-stranded RNAs, they would suffer toxic effects. These cells would also attract the attention of the immune system.
ADAR1 has been implicated in esophageal cancer by other researchers, and levels of ADAR1 have been correlated with poor survival. But the current study is the first to identify a mechanism that explains how ADAR1 is detrimental.
“We have a lot of enthusiasm that blocking ADAR1 may have direct efficacy for esophageal cancers,” Bass said, “and that ADAR1 inhibition may enhance the efficacy of cancer immunotherapy in patients with esophageal cancer.”
Beyond the results regarding ADAR1 and ERVs, the process of modeling the development of esophageal cancer via genomic engineering of organoids also revealed many other processes in esophageal cancer that could lead to new treatments.
“The way we used organoids to build cancers up from the normal cell is a powerful system for uncovering cancer-causing activities and testing therapeutic targets,” Bass asserted. “By making individual genome alterations in these models one at a time, we can see which combinations of genetic alterations lead to cancer and then determine specific mechanisms of tumor formation.”
The organoids in the current study started with overexpression of the SOX2 gene, a commonly amplified factor that promotes the development of squamous cancers.
In the study, the Bass team built a panel of organoids modeling the spectrum from normal esophagus to fully transformed cancer. The organoids revealed that when SOX2 is overactive—and two tumor suppressors are inactivated—SOX2 works with other factors to turn on an assortment of cancer-causing genes in addition to their effects upon induction of ERVs.
“While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome,” the authors of the Nature Medicine article wrote. “With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3.”
“These findings reveal new vulnerabilities in SOX2 esophageal cancers,” Bass emphasized, “that will now allow us to begin developing therapies that can precisely target the cancer cell and improve the treatment of patients.”