Toward Uncovering the Origin of Merkel Cell Carcinoma
Abstract
Merkel cell carcinoma (MCC) is an aggressive and deadly skin cancer. There is no effective treatment, and the 12-month survival rate of MCC patients is only 20%. The current standard of care in MCC is chemotherapy, which is effective but does not have a long-lasting effect, resulting in high mortality. Recent research into immunotherapy has shown promising results that are equally effective as chemotherapy with more lasting effects, but the 30%-50% of patients whose cancer does not respond are left with inadequate chemotherapy as their only option. Identification of new therapies to treat MCC is a serious unmet need and is the long-term goal of the proposed studies. Mouse models are a critical tool in developing treatments for disease. Mice are genetically pliable, allowing researchers to manipulate their DNA to understand how a tumor initiates and sustains itself in a mammalian body. Their relative physiological similarity to humans also makes them an ideal testing ground for potential therapeutic treatments before human clinical trials. There is currently no effective mouse model of MCC. In the absence of such an essential tool, translational research into treating MCC has been frustratingly limited. Human genomic studies have shown that most MCCs contain DNA from the Merkel cell polyomavirus (MCV). Asymptomatic, benign MCV infection is almost ubiquitous in the general population. However, in elderly and immunosuppressed individuals, the virus can integrate its own DNA into the host genome and use the cell’s machinery to produce two viral proteins: large T antigen (LT-Ag) and small T antigen (sT-Ag). Studies have shown that the expression of these MCV antigens is the driving force of MCC tumorigenesis. It is key to note that MCV DNA is integrated into the MCC tumor cell genome in a monoclonal pattern, meaning it is in the same location on the genome in all tumor cells. Therefore, the entire tumor originates from an individual cell, where MCV DNA is integrated. One of the unanswered questions about MCC is the identity of that original tumor-initiating cell—what type of cell can give rise to MCC upon MCV integration and antigen expression? MCC tumor cells bear a strong transcriptional resemblance to their namesake, Merkel cells, which are epidermal cells required for light touch sensations. However, expressing MCV antigens in Merkel cells in mice does not result in MCC, probably because Merkel cells are non-dividing cells. We recently identified a population of Merkel cell progenitor cells that can replenish Merkel cells during normal homeostasis. These cells are committed to Merkel cell differentiation but, unlike mature Merkel cells, are still proliferative and could give rise to a tumor. We hypothesize that these Merkel cell progenitors are the MCC tumor-initiating cells. The proposed studies are focused on the Fiscal Year 2020 Rare Cancer Research Program Research Model Focus Area. We will test our hypothesis by generating a mouse model in which MCV antigens are expressed in Merkel cell progenitors. We will analyze and characterize MCC tumor formation in these mice. Testing this hypothesis will expand our knowledge of MCC, including its cell of origin, and potentially open an avenue to new MCC treatments that target Merkel cell progenitor cells. Most exciting is that the completion of these studies will yield an animal model of MCC that can be used for preclinical drug testing, accelerating the development of lifesaving therapies for MCC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110564
Entities
People
- Idan Cohen
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army