Classical and variant Merkel cell carcinoma cell lines display different degrees of neuroendocrine differentiation and epithelial-mesenchymal transition.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer characterized by high invasiveness, early metastases and high mortality. Due to the lack of suitable animal models, most functional studies are performed using cell lines, of which some lack classical neuroendocrine growth characteristics. Here, we scrutinized the molecular characteristics of classical (cMCCs) and variant (vMCCs) cell lines by differential gene expression and the respective epigenetic regulation by microRNAs (miRs) and DNA methylation. Cutaneous squamous cell carcinoma cell lines (SCCs) were used for comparison. The most striking observation was a lower expression of epithelial-mesenchymal transition (EMT)-related genes in cMCCs, which was accompanied by higher expression of the EMT regulating miR-clusters miR-200c-141 and miR-183-96-182 as well as hypomethylation of the respective miR-loci. Experimental expression of the MCC lineage factor ATOH1 in vMCCs resulted in an increased expression of miR-200c-141 paralleled by a reduction of genes associated with EMT, thus demonstrating a connection between neuroendocrine characteristics and the lack of EMT. Together, our observations not only reinforce concerns about the use of vMCCs as proper MCC representatives, but also suggest vMCCs as cells locked in an intermediate state between neuroendocrine and epithelial differentiation.