Investigating cell of origin of merkel cell carcinoma, a historic misnomer

Summary: Abstract Body: 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 their prevalence in immunosuppressed populations, it is important to determine the cell of origin for these cancers to elucidate targetable pathways and enable novel treatment strategies. 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-biopsied MCC samples, one MCC cell line (MS-1), and 92 FFPE MCC samples, respectively, for several B-cell markers. RNA sequencing of 17 FFPE MCC samples was conducted to determine differentially expressed genes based on patient factors, identify gene co-expression networks and evaluate tumor cell enrichment. We observed heterogeneous interindividual expression of B-cell and neuroendocrine markers, including PAX5, TdT, IgA, CD19, CK20 and chromogranin A. Transcriptome analysis demonstrated differentially expressed genes based on sex and Merkel cell polyomavirus (MCPyV) status, with MCPyV+ tumors having upregulation of pathways involved in immune cell function and downregulation of those related to neuronal activity. Co-expressed gene networks highlighted enrichment of pathways involved in immune function, including B-cell differentiation, while cell type analysis highlighted enrichment for multipotent stem cells, several immune cell types, and keratinocytes. Our findings 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 MCPyV+ tumors. Our work highlights significant variability in the molecular landscape of MCCs and merits a precision medicine approach to their characterization and treatment. Richie Jeremian¹, Ivan V. Litvinov¹ 1. Research Institute of the McGill University Health Centre, Montréal, QC, Canada. Translational Studies: Cell and Molecular Biology