Investigating the cell of origin and novel molecular targets in Merkel cell carcinoma: a historic misnomer

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with the poorest prognosis, posited to be derived from Merkel cells. Emerging evidence, however, suggests other potential origins for MCC including hematological lineages. Given the high fatality of MCCs and that many arise in the immune suppressed population, often precluding the use of immunotherapy, it is important to determine the cell of origin for these cancers to elucidate targetable pathways to enable novel treatment approaches. We utilized targeted and multi-omics approaches to explore expression patterns at both the protein and RNA level of MCCs. Western blotting, immunofluorescence, and immunohistochemistry were performed for two patient-derived MCC samples, one MCC cell line, and 92 FFPE samples, respectively, for numerous B-cell markers. Further, RNA sequencing was performed on 17 FFPE patient-derived MCC samples and evaluated by principal component analysis for differentially expressed genes between samples based on sex and MCPyV status. Finally, weighted gene correlation network analysis (WGCNA) and cell type enrichment analyses were employed to determine pathway and cell type enrichment, respectively. MCC patient-derived and cell line samples heterogeneously expressed B-cell and neuroendocrine markers including PAX5, TdT, IgA, CD19, CK20, and chromogranin A. Further, transcriptome analysis demonstrated differentially expressed genes based on sex and MCPyV status. MCPyV+ tumors notably demonstrated significant upregulation of genes involved in immune cell function and downregulation of processes related to neuronal activity. Finally, WGCNA highlighted enrichment for pathways involved in immune function including B-cell differentiation. Cell type enrichment analysis highlighted enrichment for multipotent stem cells, several immune cell types, and keratinocytes. Our findings together with previous results indicate that MCCs are not derived from Merkel cells and instead from multiple or divergent cell types, including those of B-cell lineage. Further, MCC cell of origin may depend on patient and tumour specific characteristics including sex and cell type/differentiation state of a cell infected by the MCPyV. Our work highlights the need for a more personalized approach to diagnosis/characterization and treatment of MCCs given the variability of potentially targetable pathways.