Merkel cell polyomavirus is one of seven viruses known to cause cancer in humans. Infection with this virus is asymptomatic, but, rarely, it can lead to the development of Merkel cell carcinoma (MCC), an aggressive neuroendocrine cancer of the skin. Infection with this virus causes cells to express large tumor and small tumor antigens. Presence of these antigens can, in turn, deactivate the cell’s normal safeguards against becoming cancerous, leading to enhanced survival and proliferation when compared to normal cells. These mechanisms of cancer transformation are well-established and respected within the field, but one significant challenge to understanding MCC remains: No one knows which normal cells turn into the cancer.
Initially, researchers thought that MCC originates from Merkel cells in the skin. Merkel cells reside in the skin, sense light and touch, and communicate with nerves to tell the brain what they sense. Merkel cells and MCC express many of the same neuroendocrine markers, but Merkel cells cannot divide because they are terminally differentiated. MCC, like all cancers, is defined by uncontrolled cell division, meaning that Merkel cells are unlikely candidates for the cell of origin. Other cells in the skin, like epidermal and dermal stem cells, have been proposed as the cells of origin, but no research group has been able to prove that these cells can even be infected with Merkel cell polyomavirus, let alone become cancerous. So far, the only cells that researchers have been able to grow in a dish and infect with the polyomavirus are fibroblast cells. In the skin, fibroblasts create connective tissues and help cells in the outermost layer of skin stick together. But, they also cannot be the MCC cell of origin because, even when they are infected with the virus, they never become cancerous.
Fibroblasts are known as permissive cells for Merkel cell polyomavirus infection. This means that they can be infected and allow for viral replication, but they never become cancer cells. Despite this, they are still a useful model for polyomavirus infection and the physiological impacts of the large and small tumor antigens induced by viral infection. Studying viral infection in cells that do not become cancerous can also tell researchers whether the tumor antigens do the same things in non-cancer cells. Dr. Joselyn Landazuri Vinueza and her colleagues in the Galloway lab decided to use fibroblast cells to study small tumor antigen interactions.
Infecting cells with polyomavirus in a dish, while possible, is extremely difficult. The group instead decided to overexpress the small tumor antigen in fibroblast cells. Simply overexpressing the small tumor antigen would not tell the researchers what it is actually interacting with, so they fused the antigen to a biotin ligase protein. This way, proteins that are near the small tumor antigen would be tagged with a small biotin molecule. Then, the team used a strong biotin binder to pull down all the biotin-tagged proteins. From there, they used mass spectrometry to identify the proteins in their samples. This experiment identified seven new interactor proteins involved in tumor-promoting and tumor-suppressing pathways. Of these seven, δ-catenin was found to have the strongest interaction with the small tumor antigen.
Next, the group tested if the small tumor antigen in MCC cell lines also interacted with δ-catenin. They found that unlike the fibroblast cells used to identify the interaction, MCC derived small tumor antigen did not interact with δ-catenin. Despite this, the group hypothesized that δ-catenin may still be important for MCC proliferation. They knocked down the gene in MCC cell lines and found that cells without δ-catenin grew much slower than those with intact gene expression. Through RNA sequencing, they found that the presence of δ-catenin promotes the expression of genes involved in the cell cycle, and the knockdown reduced the expression of these genes. When they repeated this experiment with fibroblast cells, they found that δ-catenin had no impact on cell proliferation, highlighting distinct roles for this protein in different cell types.
The work done here reveals important clues in the quest to uncover the MCC cell of origin. For one, uncovering new small tumor antigen interactors in the permissive fibroblast cells provides a relevant environment to study these molecular mechanisms that may play a role in the Merkel cell polyomavirus lifecycle. The fact that interactions between small tumor antigen and δ-catenin also suggests that fibroblasts are not the MCC cell of origin. The group proposes that fibroblast cells allow for viral replication, and, occasionally, the virus infects a precursor for Merkel cells known as a Merkel progenitor cell. Merkel progenitors do not allow for viral replication, so the virus integrates into the host genome, causing the progenitor to become cancerous. While more mechanistic insights are necessary to confidently identify the MCC cell of origin, this work supports the idea that two distinct cell types support polyomavirus infection and oncogenesis.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Denise Galloway contributed to this work.
This work was funded by the National Institutes of Health and the Viral Pathologies and Evolution Training Grant.
Landazuri Vinueza J, Salisbury NJH, Dye KN, Roman A, Galloway DA. 2025. Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts. mBio. 16(6):e0083225. doi: 10.1128/mbio.00832-25.
Kelsey Woodruff is a PhD candidate in the Termini Lab at Fred Hutch Cancer Center. She studies how acute myeloid leukemia cells remodel the sugars on their membranes to reprogram cancer cell signaling. Originally from Indiana, she holds a bachelor's degree in Biochemistry from Ball State University. Outside of lab, you can find her crocheting and enjoying the Seattle summers.
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