Viruses impact human health in many ways and can be the underlying agents that cause cancer.
The pandemic has reminded us how pervasive viruses are in human life. We know they can cause infection, making us very sick, but did you know that about 15 percent of all human cancers worldwide may be attributed to viruses?
Drs. Paul Lieberman, professor, and Italo Tempera, associate professor, both in the Gene Expression & Regulation Program of The Wistar Institute Cancer Center, investigate the link between the Epstein-Barr Virus (EBV) and malignant transformation to find ways to treat EBV-related cancers.
EBV is a very common virus. You know it as mononucleosis, and it is spread through saliva, but also through sexual contact, blood transfusions and organ transplants. It mostly infects B cells, a type of white blood cells that produces antibodies. The majority of the world population is infected and carries the virus in a silent state for life. However, in people with compromised immune systems, EBV increases the risk of B-cell lymphomas including Burkitt’s lymphoma and Hodgkin’s lymphoma.
Since it can also infect other types of cells, this virus is not only associated with blood tumors, but also with ten percent of all gastric cancers and most cancers of the nasopharynx, the region behind the nose and above the back of the throat.
How are viruses implicated in cancer?
They are particles made up of DNA or RNA surrounded by a protein coat. With such frugality comes the lack of the necessary machinery to replicate their genome or build proteins, so viruses hijack a host cell and use its machinery to make copies of themselves. In the case of oncogenic or cancer-causing viruses, this process can meddle with the cell’s genes and derail the mechanisms that keep cell proliferation in check, leading to uncontrolled growth.
Oncogenic viruses establish chronic but latent infections that don’t cause obvious symptoms in healthy individuals, because their immune system keeps infection at bay. In immunocompromised people, however, viruses are more likely to cause malignancies.
One approach to control EBV infection is by interfering with the complex and dynamic patterns of how viral genes are switched on or off — a process known as gene expression. The Tempera lab has explored the role of gene expression in the regulation of EBV latency, unveiling some viral and host cell factors that play key roles in regulating these patterns.
An EBV protein called latent membrane protein 1 (LMP1) is essential for the virus’s ability to make B cells cancerous.
The Tempera lab studies just how this protein affects the host cells. They discovered that LMP1 affects the function of an enzyme called poly(ADP-ribose) polymerase 1 (PARP1) and that inhibiting this protein suppresses malignant transformation, uncovering an important role of PARP1 in EBV-induced oncogenesis.
In a recent paper1, Tempera and colleagues demonstrated that LMP1 causes a switch in how infected cells produce the building blocks of fat that support tumorigenesis and cancer progression. Researchers also showed that targeting these metabolic changes could be an effective therapeutic strategy to treat EBV-associated cancer and that PARP1 inhibitors offset the metabolic changes caused by LMP1 that drive tumorigenesis.
"We have uncovered a potential new use for PARP inhibitors, which are currently used to treat recurrent ovarian cancers in women who have defects in their DNA repair system," said Dr. Tempera. "Repurposing existing drugs saves time and money in the process of creating new therapies."
Dr. Tempera joined Wistar as an associate professor in 2020, but that was not his first time working at the Institute. He had trained as a postdoctoral fellow in the Lieberman lab, which helped him launch his career in cutting-edge research on the epigenetic mechanisms underlying EBV infection. Returning to Wistar with his lines of research as an established investigator, he strengthened our program on virology and cancer.
"The outstanding scientific environment and technological support that benefited me during my training are a strong asset to further expand my research program."
The lab of his mentor Dr. Lieberman is a reference point for EBV research as they have made seminal discoveries in the field and described several mechanisms that control replication and gene expression in latent EBV infection. One focus of their research is the Epstein-Barr nuclear antigen 1 (EBNA1) protein that is essential for efficient viral DNA replication. The team has been pursuing the development of small molecule inhibitors of EBNA1 as potential treatment against EBV-associated malignancies.
One of the lab’s latest studies2 led to an important basic discovery in the field, expanding the understanding of EBNA1’s function and providing new possibilities for inhibiting EBNA1 activity as an anticancer strategy.
The link between virus infection and human cancer is a complicated matter to unravel and has been studied for more than 100 years. The research underway in the Tempera and Lieberman labs is crucial to understanding the role viruses play in malignant transformation and hopefully finding future treatments to halt this process.
1 Epstein-Barr Virus-Encoded Latent Membrane Protein 1 and B-Cell Growth Transformation Induce Lipogenesis through Fatty Acid Synthase, J Virol, 2021
2 Cell-cycle-dependent EBNA1-DNA crosslinking promotes replication termination at oriP and viral episome maintenance, Cell, 2021