Merkel cell carcinoma (MCC) is a rare but lethal cancer with the highest case-by-case fatality rate among all skin cancers. 80% of cancers are associated with the Merkel cell polyomavirus (MCPyV). 20% of MCCs are virus negative.,Recent epidemiological data suggest that there are important, clinically relevant differences between these two subtypes of MCC.,Recent studies in cancer genomics, mouse genetics, and virology experiments have transformed our understanding of MCC pathophysiology.,Importantly, dramatic differences in the genetics of these two MCC subtypes suggest fundamental differences in their pathophysiology.,We review these recent works and find that they provocatively suggest that MCPyV-positive and MCPyV-negative MCCs arise from two different cells of origin: the MCPyV-negative MCC from epidermal keratinocytes and the MCPyV-positive MCC from dermal fibroblasts.,If true, this would represent the first cancer that we are aware of that evolves from cells of origin from two distinct germ layers: MCPyV-negative MCCs from ectodermal keratinocytes and MCPyV-positive MCCs from mesodermal fibroblasts.,Future epigenetic experiments may prove valuable in confirming these distinct lineages for these MCC subtypes, especially for the clinical importance the cell of origin has on MCC treatment and prevention.
Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor frequently associated with clonal integration of a polyomavirus, MCPyV, and MCC tumor cells express putative polyomavirus oncoproteins small T antigen (sTAg) and truncated large T antigen (tLTAg).,Here, we show robust transforming activity of sTAg in vivo in a panel of transgenic mouse models.,Epithelia of pre-term sTAg-expressing embryos exhibited hyperplasia, impaired differentiation, increased proliferation and apoptosis, and activation of a DNA damage response.,Epithelial transformation did not require sTAg interaction with the PP2A protein complex, a tumor suppressor in some other polyomavirus transformation models, but was strictly dependent on a recently-described sTAg domain that binds Fbxw7, the substrate-binding component of the SCF ubiquitin ligase complex.,Postnatal induction of sTAg using a Cre-inducible transgene also led to epithelial transformation with development of lesions resembling squamous cell carcinoma in situ and elevated expression of Fbxw7 target proteins.,Our data establish that expression of MCPyV sTAg alone is sufficient for rapid neoplastic transformation in vivo, implicating sTAg as an oncogenic driver in MCC and perhaps other human malignancies.,Moreover, the loss of transforming activity following mutation of the sTAg Fbxw7 binding domain identifies this domain as crucial for in vivo transformation.