Lipid droplet organized metabolic vulnerabilities in melanoma: from the MITF low state to ferroptosis sensitization.

Melanoma's ability to progress and develop resistance to therapies are the result of both genotypic changes and substantial levels of adaptability at the phenotypic and metabolic level. One of the most clinically relevant adaptive states is the microphthalmia associated transcription factor MITF low, which has been correlated with de-differentiation, invasion potential and drug tolerance, as well as altered redox status. As important regulators of this adaptation, lipid droplets have become involved in coordinating fat stores and mobilization, organelle signaling, membrane lipid composition and protection against oxidative stress. However, their role is context-dependent. For example, under certain melanoma conditions lipid droplets are able to isolate poly-unsaturated fatty acids (PUFA) from membrane phospholipids thus preventing ferroptosis. Under other conditions lipid droplet degradation through processes such as lipolysis, lipophagy or inter organelle lipid transfer results in the release of potentially oxidizable substrates increasing ferroptotic sensitivity. This review describes the impact of MITF-loss on melanoma cell lipid acquisition, desaturation, triglyceride synthesis and fatty acid oxidation, as well as phospholipid remodeling, antioxidant defense mechanisms and iron compartmentalization. An emphasis is placed on understanding the roles of several enzymes including DGAT1/2, SCD1, ACSL3, ACSL4, LPCAT3, MBOAT1/2, CPT1A, ACOX1, GPX4, FSP1 and lysosome-mitochondrial iron trafficking in defining whether melanoma cells are susceptible to or resistant to ferroptotic cell death. Additionally, this review provides an overview of clinical approaches that target protective lipid droplet programs, enhance membrane PUFA content, block compensatory fatty acid oxidation pathways and/or compromise ferroptosis-defensive systems. A major conclusion from this review is that the MITF low state is not uniformly ferroptotic; rather susceptibility depends upon a balance among lipid sequestration, membrane remodeling, oxidative metabolism, antioxidant defenses and cellular iron content. Identifying these state-specific metabolic requirements should provide a rationale for developing biomarker guided combinations of MAPK targeted therapy and immunotherapy-based treatments to selectively kill persistent populations of melanoma.