Comprehensive single-cell transcriptomic analysis of embryonic melanoblasts uncovers lineage-specific mechanisms of melanoma metastasis and therapy resistance

Across cancers, tumor cells can resemble embryonic cell states that may allow them to metastasize and evade therapies. Melanoma is a cancer of the melanocyte that exhibits a wide range of transcriptional states characterized by alterations in embryonic melanocyte gene expression patterns. How these states and their functions are related to the embryonic precursors of melanocytes, the melanoblasts, is unknown. Here, we present the first high-resolution single-cell RNA-seq profiles of embryonic melanocytic lineages in mice. We discover a diverse array of transcriptional cell states in this lineage and confirm, for the first time at the single-cell level, that melanocytes arise from Schwann-cell precursors (SCPs), a highly plastic cell population, via a newly described intermediate mesenchymal-like state. Via novel computational strategies to map these developmental cell states to metastatic melanoma, we find that SCP-resembling tumors are associated with exclusion of the immune cells and non-response to immune checkpoint blockade. In contrast, a higher mesenchymal profile underlies immune dysfunction and resistance to BRAF-inhibition therapy. We also carry out the first time-resolved single-cell RNA-seq study of early melanoma metastatic colonization, demonstrating that melanoma cells activate a SCP program transiently during early metastatic colonization. Finally, we discover a hybrid lineage state that resembles multiple melanocytic lineages simultaneously and is enriched in melanoma cells during metastatic seeding and in therapy resistance. Our work reveals that the lineage-specific mechanisms underlie melanoma progression/evolution, including early metastatic colonization and therapeutic resistance.