In humans, epidermal melanocytes are responsible for skin pigmentation, defence against ultraviolet radiation and the deadliest common skin cancer, melanoma. Although there is substantial overlap in melanocyte development pathways between different model organisms, species-dependent differences are frequent and the conservation of these processes in human skin remains unresolved. Here, we used a single-cell enrichment and RNA-sequencing pipeline to study human epidermal melanocytes directly from the skin, capturing transcriptomes across different anatomical sites, developmental age, sexes and multiple skin tones. We uncovered subpopulations of melanocytes that exhibit anatomical site-specific enrichment that occurs during gestation and persists through adulthood. The transcriptional signature of the volar-enriched subpopulation is retained in acral melanomas. Furthermore, we identified human melanocyte differentiation transcriptional programs that are distinct from gene signatures generated from model systems. Finally, we used these programs to define patterns of dedifferentiation that are predictive of melanoma prognosis and response to immune checkpoint inhibitor therapy.

在人类中，表皮黑色素细胞负责皮肤色素沉着、防御紫外线辐射和最致命的常见皮肤癌黑色素瘤。尽管不同模式生物之间的黑素细胞发育途径存在大量重叠，但物种依赖性差异很常见，并且这些过程在人类皮肤中的保存仍未解决。在这里，我们使用单细胞富集和 RNA 测序管道直接从皮肤研究人类表皮黑色素细胞，捕获不同解剖部位、发育年龄、性别和多种肤色的转录组。我们发现了黑色素细胞亚群，这些亚群表现出在妊娠期间发生并持续到成年期的解剖部位特异性富集。富含掌侧的亚群的转录特征保留在肢端黑色素瘤中。此外，我们确定了与模型系统生成的基因特征不同的人类黑素细胞分化转录程序。最后，我们使用这些程序来定义可预测黑色素瘤预后和对免疫检查点抑制剂治疗反应的去分化模式。