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

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.

Keywords: EMT; melanocyte differentiation; melanoma metastasis; pluripotent embryonic stem cells.

Figure 1

Comparison of embryonic melanocyte generation and the metastatic process in malignant melanoma. Left panel depicts neural tube formation and subsequent delamination. Migration of neural crest cells is indicated following terminal differentiation after invasion into the epidermis. Right panel depicts primary melanoma growth and subsequent migration and invasion of cells until melanoma cells colonize distant metastatic sites.

Figure 2

Dynamic process of phenotype switching in human melanoma. Proliferative melanoma cells become invasive and migrative upon stimulation with extrinsic factors. In turn, invasive melanoma cells switch to a more differentiated and proliferative phenotype when treated with ascorbic acid (AA), the hormone a-MSH or the growth factor FGF-2. Therapeutic options include (A) treatment of invasive cells with epithelial mesenchymal transition (EMT) inhibitors or differentiation promoters and (B) treatment of proliferative cells with cell cycle or kinase inhibitors. Importantly, therapy should stop the continuous switching between cellular states. AA: Ascorbic Acid, a-MSH: α-Melanocyte stimulating hormone, FGF2: basic fibroblast growth factor, TGFb: transforming growth factor beta, IL6: interleukine 6.