Cutaneous melanoma represents one of the deadliest types of skin cancer.,The prognosis strongly depends on the disease stage, thus early detection is crucial.,New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade.,However, intrinsic and acquired resistance is still a challenge.,In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity.,First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC).,Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance.,Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3.,These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
Cancer-secreted exosomal miRNAs regulates the biological processes of many tumours.,The serum level of exosomal miR-106b-5p is significantly increased in melanoma patients.,However, the role and molecular mechanisms of exosomal miR-106b-5p in melanoma remains unclear.,Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-106b-5p and EphA4 in melanoma tissues.,Transmission electron microscopy (TEM) and western blotting were used to identify exosome.,QRT-qPCR and Cy3-labelled miR-106b-5p were used to demonstrated the transmission of melanoma cell-secreted exosomal miR-106b-5p.,Western blotting, Immunofluorescence, adhesion, transwell and scratch wound assay were used to explore the role of exosomal miR-106b-5p in melanocytes.,Luciferase reporter assays and RNA-Chromatin Immunoprecipitation (ChIP) assay were used to confirm whether erythropoietin-producing hepatocellular carcinoma receptor A4 (EphA4) was a direct target of miR-106b-5p.,We found that miR-106b-5p levels were increased in melanoma tissue, and high miR-106b-5p expression is an independent risk factor for the overall survival of patients with melanoma. miR-106b-5p is enriched in melanoma cell-secreted exosomes and transferred to melanocytes.,Exosomal miR-106b-5p promotes the epithelial-to-mesenchymal transition (EMT), migration, invasion and adhesion of melanocytes.,Exosomal miR-106b-5p exerted its role by targeting EphA4 to activate the ERK pathway.,We demonstrated that exosomal miR-106b-5p promoted melanoma metastasis in vivo through pulmonary metastasis assay.,Thus, melanoma cell-secreted exosomal miR-106b-5p may serve as a diagnostic indicator and potential therapeutic target in melanoma patients.,The online version contains supplementary material available at 10.1186/s13046-021-01906-w.