Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress
Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our analysis of gene expression profiles from a large panel of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be sub-classified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase mediated resistance to MAPK targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs presents an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies. Melanoma cells are present at different differentiation states and have the ability to dedifferentiate under cellular stress. This has important therapeutic implications as dedifferentiation contributes to intrinsic and acquired resistance to MAPK pathway inhibitors, and occurs as a response to inflammatory signaling during immunotherapy. Therefore, targeting dedifferentiation is a logical approach to strengthen these current therapeutic strategies. Here we categorize melanoma differentiation as four distinct stepwise stages and identify a heightened sensitivity to ferroptosis induction with the degree of differentiation. Our results further define tumor differentiation as an important parameter for patient stratification, and propose a new and highly orthogonal component to add to existing therapeutics, namely enhancing targeted signaling inhibition and immune therapies by synthetic lethal induction of ferroptosis.