Merkel cell development and Merkel cell carcinoma
Merkel cell carcinoma (MCC) is one of the most aggressive and deadly forms of skin cancer. Although MCC tumors are rare, their incidence has tripled in recent years. Current MCC treatments involve surgery and chemotherapy, but the response to these treatments is poor, with a 12-month patient survival rate of only 20%. Thus, the development of novel therapeutic strategies for the treatment of MCC is critical.
Human genomic studies have shown that more than 80% of MCC tumors contain DNA from the Merkel cell polyomavirus (MCV). In vitro studies showed that the expression of MCV’s small T antigen (sT-Ag) leads to the transformation of human cells, whereas ablation of sT-Ag from MCC cell lines inhibits their proliferation. However, testing the in vivo relevance of MCV oncogenes for MCC formation has proven difficult. While Merkel cells have been shown to originate from embryonic epidermal stem cells, the expression of MCV oncogenes in these cells results in squamous cell carcinoma, rather than MCC. Although this confirms the tumorigenic potential of MCV oncogenes, it also shows that this modeling strategy does not target the proper cell population that is competent to produce MCC.
There has been debate as to whether all epidermal progenitors can give rise to Merkel cells, or a specific population of cells called Merkel cell progenitors exists that has this potential. In the lab, we aim to dissect the developmental program controlling Merkel cell formation. Uncovering these mechanisms is of major importance not only for the characterization of the Merkel cell lineage, but also for testing the potential of these cells to form MCC.
Figure: Whole mount immunofluorescence staining for Keratin 8 (K8) + Merkel cells in P0 mouse back skin. (Image appears in Perdigoto et al., 2016, PLOS Genetics).
Perdigoto CN, Dauber KL, Bar C, Tsai P-C, Valdes VJ, Cohen I, et al. (2016) Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell