LAUSR

Cancer cells reprogram their metabolism using different strategies to meet anabolic demands to maintain growth and survival. Defining the molecular and genetic determinants of these metabolic programs, including ROS metabolism, is critical to successfully exploit them for therapy. PGC1a is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress and reprograms metabolism to influence drug sensitivity and survival. For example, a subset of melanomas is highly dependent on PGC1a and activates a powerful ROS detoxification capacity that enables survival. Interfering with the ROS detoxification system provides important vulnerabilities of melanoma cells. Importantly, PGC1a is also linked to mitochondrial heterogeneity that allows selective outgrow of cells, both during natural selection and drug-targeted resistance, that exhibit an invasive and aggressive phenotype. Mechanistically, PGC1a establishes a series of transcriptional networks that execute cellular functions including survival and invasion that are central to melanoma progression and therapy responses. In addition, PGC1a also maintain metabolic-dependent epigenetic states that are essential to melanoma progression. As it relates to ROS detoxification capacities these networks are associated with genes that allowed cell reprogramming and survival. The mitochondrial heterogeneity defines different ROS detoxification phenotypes, however the implication of these unique phenotypes to melanoma progression is unknown, but it is likely to impact the fate of melanoma cells including programs of differentiation, growth, survival and invasion.