UCLA

Among the numerous changes associated with the transformation to cancer, cellular metabolism is one of the first discovered and most prominent. Cancers were thought to be driven by metabolic changes including increased glycolysis and lactate generation. To that end, it was previously established that inhibition of pyruvate oxidation can promote glycolysis, and in some cases promote tumorigenesis. However, studies have identified cancers are metabolically flexible and can use multiple nutrients to sustain their growth. We previously showed that inhibition of glycolysis in cutaneous squamous cell carcinoma (SCC) initiating cells had no effect on tumorigenesis, despite the perceived ubiquity of the Warburg effect, which was thought to drive carcinogenesis. Instead, these SCCs were metabolically flexible and sustained growth through glutaminolysis, another metabolic process frequently implicated to fuel tumorigenesis in various cancers. Here we aim to understand metabolic flexibility in two types of skin cancer, SCC and melanoma. In SCC we focused on glutaminolysis and genetically blocked this process through glutaminase (GLS) deletion in SCC cells of origin. Genetic deletion of GLS had little effect on tumorigenesis due to the upregulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We went on to show that posttranscriptional regulation of nutrient transporters appears to mediate metabolic flexibility in this SCC model. To define the limits of this flexibility, we genetically blocked both glycolysis and glutaminolysis simultaneously and found that this abrogation of both of these carbon utilization pathways was enough to prevent both papilloma and frank carcinoma. In melanoma, we explored the role of pyruvate oxidation ability to drive melanoma formation through the deletion of mitochondrial pyruvate carrier 1 (Mpc1) in melanoma initiating cells. Using the Braf/Pten model, the best model available to study melanoma in vivo, we find that deletion of Mpc1 decreases melanoma formation. Although different models, these data point towards the treatment of cancer through metabolic manipulation and complete cancer abrogation will require multiple interventions on distinct pathways.