Adaptations of lipid metabolism in low-grade clear cell renal cell carcinoma are linked to cholesteryl ester accumulation.

Clear cell renal cell carcinoma (ccRCC) is characterized by the accumulation of high quantities of lipids in cytoplasmic lipid droplets. Owing to the tissue heterogeneity of ccRCC, adjacent biopsies from a tumor can diverge substantially in molecular characteristics. To elucidate metabolic alterations leading to extensive lipidomic changes in grade 2 human nephrectomies, we applied a dual lipidome-transcriptome analytical procedure that allows performing correlational studies of the two datasets. Linked to the mean 100 fold increase of esterified cholesterol (ChE) in ccRCC we found multiple significant correlations between ChE and the main membrane lipids that might be mediated by an increased capacity for lipid hydrolysis linked to lysosomes and the endoplasmic reticulum.Our results suggest that the accumulation of ChE from extracellular sources might be a determinant metabolic flux in low-grade ccRCC. ChE mobilization by non-canonical hydrolytic systems might confer increased metabolic flexibility to obtain free cholesterol and fatty acids. Based on correlations between lipidome and lipometabolic transcriptome, this study provides new perspectives for evaluating pharmacological lipid management as a future therapeutic approach for low-grade ccRCC treatment.