Single cell analysis of human site-specific melanocyte differentiation and the decoding of developmental programs in melanoma

Epidermal melanocytes are present throughout the skin, one of the largest organs with distinct anatomical, morphological and functional characteristics. Clear differences in melanocytic disease manifestation and phenotype exist across different anatomical locations. Here, we investigate human melanocyte heterogeneity during development, homeostasis, and disease progression using single cell RNA sequencing of freshly isolated human fetal, neonatal, and adult skin from a demographically diverse cohort. Comparative analysis across developmental stages and between anatomical sites revealed distinct subclasses of melanocytes from lineages that diverge early in human development. Using differentiation programs delineated from healthy melanocytes, we identified melanoma gene expression signatures that are developmental in origin and are re-acquired during disease, signatures that are unique to melanoma progression, as well as signatures that offer prognostic value. This dataset provides a valuable resource for further investigations of the melanocytic lineage in health and disease.