Insights into Differentiation of Melanocytes from Human Stem Cells and Their Relevance for Melanoma Treatment

SIMPLE SUMMARY: The reactivation of embryonic developmental programs is crucial for melanoma cells to grow and to metastasize. In order to understand this process better, we first summarize the melanocytic differentiation process both in vivo and in vitro. Secondly, we compare and highlight important similarities between neural crest cell fate during differentiation and tumor cell characteristics during melanoma mestastasis. Finally, we suggest possible therapeutic targets, which could be used to inhibit phenotype switching by developmental cues and hence also suppress the metastatic melanoma spread. ABSTRACT: Malignant melanoma represents a highly aggressive form of skin cancer. The metastatic process itself is mostly governed by the so-called epithelial mesenchymal transition (EMT), which confers cancer cells migrative, invasive and resistance abilities. Since EMT represents a conserved developmental process, it is worthwhile further examining the nature of early developmental steps fundamental for melanocyte differentiation. This can be done either in vivo by analyzing the physiologic embryo development in different species or by in vitro studies of melanocytic differentiation originating from embryonic human stem cells. Most importantly, external cues drive progenitor cell differentiation, which can be divided in stages favoring neural crest specification or melanocytic differentiation and proliferation. In this review, we describe ectopic factors which drive human pluripotent stem cell differentiation to melanocytes in 2D, as well as in organoid models. Furthermore, we compare developmental mechanisms with processes described to occur during melanoma development. Finally, we suggest differentiation factors as potential co-treatment options for metastatic melanoma patients.