Are there multiple cells of origin of Merkel cell carcinoma?

Abstract

Merkel cell carcinoma (MCC) is a rare but lethal cancer with the highest case-by-case fatality rate among all skin cancers. Eighty percent of cancers are associated with the Merkel cell polyomavirus (MCPyV). Twenty percent 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.

Figure 1

(A) Mutational Burden of Skin and Selected Non-Skin Cancers for Comparison Blue bars = dominant UV signature. Red bars = non-dominant/lack UV signature. BCC = Basal Cell Carcinoma; SCC = Cutaneous Squamous Cell Carcinoma^, ; MCPyV− or + MCC = Merkel Cell Polyoma Virus negative or positive Merkel Cell Carcinoma^{, ,} ; AK = Actinic Keratosis; Cutan-Mel = Cutaneous Melanoma; Lung SCC = Lung Adenocarcinoma; HNSCC = Head and Neck Squamous Cell Carcinoma^, ; KC = Keratinocyte^, ; CTCL = Cutaneous T cell Lymphoma^, ; Acral Melanoma^, ; Breast CA = Breast Adenocarcinoma (B) Schema Depicting Model of Convergent Development of MCPyV− and MCPyV+ MCC. In the epidermis, a keratinocyte precursor is depicted undergoing UV mutagenesis, positive selection, mutation in Rb and p53, and neuroendocrine transdifferentiation resulting in MCPyV− MCC. In the dermis, MCPyV enters dermal fibroblasts, undergoes LT truncation leading to viral repression of Rb, sustained ST expression, and eventual virus-induced neuroendocrine transdifferentiation resulting in MCPyV+ MCC.