Clear cell renal cell carcinoma (ccRCC) is the most devastating form of human kidney cancer and is marked by significant accumulation of lipids and dysregulated glutathione metabolism. However, the role of lipids in ccRCC pathogenesis is poorly understood despite evidence that aspects of lipid metabolism correlate with worse patient survival. Although glutathione metabolomics signatures can be strong predictors of ccRCC metastasis and progression, we do not have a clear understanding of glutathione and redox biology in ccRCC. This proposal aims to dissect the molecular underpinnings of ccRCC lipid metabolism, specifically fatty acid biosynthesis, and the interplay of lipid metabolism with glutathione metabolism in ccRCC. Glutathione metabolism and lipid metabolism are seemingly linked through the reducing equivalent NADPH. NADPH is required to regenerate reduced glutathione (GSH) but it also required to synthesize fatty acids. We will utilize stable isotope tracing in human patients and patient derived xenograft (PDX) ccRCC mouse models to accomplish this goal.
The Specific Aims of this proposal intend to (1) compare the contribution of fatty acid biosynthesis and extracellular fatty acid uptake to ccRCC lipid accumulation, (2) test how fatty acid metabolism contributes to redox and glutathione homeostasis, and (3) understand ccRCC lipid metabolism in living human patients. We will use stable isotope infusions of 13C-labeled metabolites to identify and pinpoint pathways of lipid metabolism that are highly active in human ccRCC patients. We will then use PDX models that faithfully recapitulate clinical ccRCC to systematically dissect the observations we see in humans. Altogether, these Aims will generate new data and insights into an underexplored area of ccRCC biology with unprecedented relevance to human disease. The findings of this proposal could point to a mode of metabolic reprogramming applicable to multiple cancer types and have strong implications for therapeutic intervention for ccRCC patients.
Substantial fat accumulation is a hallmark feature of clear cell renal cell carcinoma (ccRCC), the most common form of human kidney cancer. However, the function of fat in ccRCC is unknown despite the fact that high expression of fatty acid synthesis enzymes correlates with worse survival in human ccRCC patients. We will test how fat accumulate in ccRCC and the metabolic function of fat accumulation in supporting ccRCC tumor growth in preclinical models and human patients.