Late stage melanoma is hallmarked by low NLGN4X expression leading to HIF1A accumulation.

BACKGROUND: Despite ongoing research and recent advances in therapy, metastatic melanoma remains one of the cancers with the worst prognosis. Here we studied the postsynaptic cell adhesion molecule Neuroligin 4X (NLGN4X) and investigated its role in melanoma progression. METHODS: We analysed histologic samples to assess the expression and predictive value of NLGN4X in human melanoma. The oncogenic role of NLGN4X was determined by loss or gain-of-function experiments in vitro as well as by analysis of tumorspheres, which were grafted to human skin organoids derived from pluripotent stem cells. Whole genome expression analysis and validation experiments were performed to clarify the molecular mechanism. RESULTS: We identified that suppression of NLGN4X down regulated the prefoldin member Von Hippel-Lindau binding protein 1 (VBP1). Moreover, loss of VBP1 was sufficient for accumulation of HIF1A and HIF1A signalling was further shown to be essential for the acquisition of migratory properties in melanoma. We re-established NLGN4X expression in late stage melanoma lines and observed decreased tumour growth after transplantation to human skin organoids generated from pluripotent stem cells. In line, we showed that high amounts of NLGN4X and its target VBP1 in human patient samples had a beneficial prognostic effect on patient survival. CONCLUSION: In view of these findings, we propose that decreased amounts of NLGN4X are indicative of a metastatic melanoma phenotype and that loss of NLGN4X provides a novel mechanism for HIF induction.

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

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.