A developmental cellular hierarchy in melanoma uncouples growth and metastatic phenotypes

Although melanoma is notorious for its high degree of heterogeneity and plasticity, the origin and magnitude of cell state diversity remains poorly understood. Equally, it is not known whether melanoma growth is supported by a subfraction of Melanoma Stem-like Cells (MSCs) and if so, whether MSCs and Metastasis-Initiating Cells (MICs) represent overlapping, interchangeable, or distinct cell populations. By combining single-cell gene expression profiling, multicolour lineage tracing and quantitative modelling, we developed a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states during primary tumour growth and metastatic dissemination in a clinically-relevant mouse model of melanoma. We show that melanoma growth and metastatic dissemination are fuelled, respectively, by two transcriptionally and spatially distinct melanoma subpopulations. Our findings implicate a hierarchical model of tumour growth that is supported by a population of cancer stem-like cells, which reside in a perivascular niche and exhibit a transcriptomic signature of pre-migratory neural crest cells established transiently during embryonic development. Metastatic dissemination is, instead, driven by a “mesenchymal-like” subpopulation, which preferentially accumulates at the invading front of primary lesions. We identified the transcription factor Prrx1 as a driver of the mesenchymal-like melanoma phenotype, and demonstrate that this population fuels metastatic dissemination to lymph nodes and distant organs through an EMT-MET-like continuum. These results will pave the way for the development of strategies that detect and, ultimately, intercept melanoma before its dissemination to vital organs.