Phenotypic distribution of the stem-like melanoma initiating state depends on CDKN2A status

Many cancers contain distinct tumor-initiating cell populations. However, the existence of distinct stem-like melanoma initiating cells and their contribution to tumorigenesis remains contested1-5. To identify this cell population in melanoma, we used quantitative single cell approaches linking gene expression, genotype and phenotype in melanoma cells, and observed that bidirectional interconversion between tumor-initiating and differentiated non-tumorigenic states establishes distinct phenotypic equilibria dependent on genotype. Genetic loss of the CDKN2A locus corresponds to a uniform adoption of a neural crest stem cell (NCSC) like tumor-initiating state. Exposure to a putative chemopreventative -melanocyte stimulating hormone (MSH) analog can substitute for CDKN2A loss and shift phenotype distribution toward the tumor-initiating state. Alarmingly, in vivo application of the analog is sufficient to induce tumorigenesis in otherwise non-tumorigenic populations. Our results demonstrate that dynamic stemness in melanoma is dependent on secondary mutation status, highlighting the need to incorporate genomic characterization when developing potential chemopreventative agents.