The study of tumor viruses — or viruses known to trigger cancer — dates back to a century-old discovery of a virus that caused cancer in chickens. Researchers have since discovered seven tumor viruses that impact humans, including well-known names like hepatitis B and C, and human papillomavirus (HPV).
Today tumor viruses are implicated in as many as 20 percent of all human cancers. Yet many of their oncogenic mechanisms remain shrouded in mystery.
Megan Spurgeon, an investigator at Morgridge’s Rowe Center for Research in Virology, studies HPV as well as the latest addition to this perilous list: Merkel cell polyomavirus (MCPyV). While this virus is incredibly common and usually harmless, it can trigger a rare and deadly form of neuroendocrine cancer in the skin called Merkel cell carcinoma (MCC). About 3,000 Americans are diagnosed annually, although MCC incidence is rising.
Spurgeon discussed her lab’s approach to studying this virus, including the development of preclinical models that can help better understand the virus-host interactions that could ultimately give rise to the devastating disease. The following interview has been edited for clarity.
How did Merkel cell research come on your radar, and how much do we know about MCPyV?
When I joined UW–Madison Professor Paul Lambert’s lab at the McArdle Laboratory for Cancer Research in 2010 to study human papillomavirus, MCPyV had just been discovered in 2008. At the time, my postdoc challenge was to look into this expanding repertoire of virus-associated cancers. I was tasked with developing a mouse model to study if and how the MCPyV T antigens — the viral proteins that the virus expresses — give rise to Merkel cell carcinoma in a mouse model. It has been valuable to have my experience in other tumor viruses because we’re learning there are a lot of parallel pathways these viruses use in how they cause cancer.
With MCPyV, we know the virus is ubiquitous from seroprevalence studies. By swabbing the skin of healthy individuals, it seems to be a part of our natural skin flora, and that we acquire it early in childhood. It seems to be asymptomatic, even when first infected with it. And that’s consistent with other microbes that are part of our flora — usually we don’t even know they’re there.
Do we understand the paradox between the virus being literally everywhere, but its related cancer remaining extremely rare?
We don’t know why the associated cancer is rare, but we do know the integration of viral DNA [into the host genome] is really a dead end for viral replication. If you think about it from the virus’s perspective, there’s really no benefit integrating into the host. And if there was benefit, we would be in much bigger trouble. So it’s actually an accident, quote-unquote, that the virus integrates.
But when the viral genome integrates, you no longer make new virus, but you still have these viral proteins with functions that are doing everything that would cause cancer, such as cell proliferation and dysregulation of the cell cycle. Integration is usually thought to be one of the last straws before these viruses ultimately give rise to cancer.
What are the challenges of studying a rare disease like MCC?
Obviously, funding is always going to be an issue, but there is also a lack of technical resources like reagents, antibodies or other tools that we would use in lab. Another aspect of rare cancer research is the difficulty of accessing samples.
Models are also important. My lab has developed and we continue to advance preclinical in vitro models, as well as in vivo models, to study specifically how this virus and its proteins cause cancer and lead to the development of Merkel cell carcinoma. As with many other kinds of neuroendocrine cancers, we’re hoping we can find good early MCC biomarkers to help detect these cancers before they become advanced. We’re also using the virus itself as a tool to learn about pathways in the cells and tissues that it infects.
Specifically for MCC, awareness of the disease is also improving, in part owing to Jimmy Buffett’s death from MCC in 2023. And while there’s always kind of a divide between basic researchers and the clinicians, the Merkel cell carcinoma field in particular has done a really good job bringing those groups together. For example, The Hutch Cancer Institute started the MC3 Collaborative where they’re trying to connect basic researchers with clinicians. It’s also a good resource for reagents and tools like tissue samples or clinical samples.
Are virus-associated cancers on the rise?
I think it depends on the virus and the type of cancer. The incidence of Merkel cell carcinoma is rising, in Wisconsin and the United States and worldwide. There could be a lot of different reasons for that. One is, people are living longer. They’re being exposed to more UV radiation from being out in the sun. There are oropharyngeal carcinomas caused by HPV that are increasing as well. And in the case of HPV, there are prophylactic vaccines, but it’s not always accessible in other parts of the world or taken in those parts where it is. As a whole, I would say, yes, across the world, they are increasing, but there’s some nuance there between the different viruses and different cancer types.
What are other areas of interest in your research?
My lab, specifically a Cancer Biology graduate student Tejas Sabu, is working under the hypothesis that this virus infects a skin cell and reprograms it into another cell type that gives rise to cancer. That is unique. With other tumor viruses, for example, HPVs infect a squamous cell and that leads to squamous cell carcinoma. And so, for instance, if we find out that MCPyV infects an epithelial cell and rewires it to become a neuroendocrine cell, and that gives rise to MCC — our discoveries for this cancer could have implications related to the early stages of other neuroendocrine cancers that aren’t associated with MCPyV.
We’re also trying to understand the parallels between HPV and MCPyV. As one example, we are studying the ways in which these viruses remodel the proteins that help replicate our DNA in order to benefit their own replication, and in doing so, could lead to things like DNA damage, which when left unrepaired can be mutagenic and lead to cancer. That’s currently the work of Morgridge Postdoc Chris Collins, who is co-mentored by myself and Dr. Kavi Mehta at UW-Madison. He’s trying to figure out both the similarities and differences between these two viruses and how they interact with that DNA replication machinery.
One of the most interesting things about viruses in general, is that they are disease-causing entities, but they’re also tools, and have been for more than a century. They have the pathways in our cells figured out, so we just have to follow them. Shine the flashlight into the cell and learn about it at the same time we learn about the virus.