The complex conundrum of Merkel cell carcinoma cellular ancestry

Merkel cell carcinoma (MCC) is a rare but lethal skin neoplasm, caused, in approximately 80% of cases, by the genomic integration of Merkel cell polyomavirus (MCPyV) and the expression of viral oncoproteins small T (sT) and large T (LT) antigens. Virus-negative MCCs exhibit extensive UV-induced mutations. Although there is a growing understanding of MCC pathogenesis, the cellular origin of MCC remains a topic of intense investigation and debate. In this perspective, we will provide a description and discussion of the current theories regarding the cellular ancestry of MCC. The most recent findings point in favor of a potential epithelial origin of MCC. MCPyV integration likely occurs in an epithelial precursor cell prior to MCPyV-driven clonal expansion, while the same originating cell type may undergo a specific molecular switch that drives neuroendocrine differentiation, leading to UV-mutated, virus-negative MCCs. Identifying the cellular origin of MCC is crucial for developing accurate pre-clinical models and advancing clinical applications.