Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase (SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

Prognostic Impact of Membranous/Nuclear Epidermal Growth Factor Receptor Localization in Clear Cell Renal Cell Carcinoma

“…In support of the involvement of bioenergetic alterations in CCRCC biology, overexpression of NDUFA4L2 in CCRCC blocks oxidative phosphorylation, reduces ROS production, and increases cellular antioxidants levels promoting progression and drug resistance [40]. Recently, Lucarelli et al identified a lipid metabolism reprogramming associated with a switch in adipogenic gene signatures in CCRCC, with accumulation of very long-chain FAs and PUFAs, sustained by overexpression of SCD1 and ELOVLs [41].…”

Renal Lipid Metabolism Abnormalities in Obesity and Clear Cell Renal Cell Carcinoma

“…Alterations of lipid metabolism described in ccRCC include increased uptake of extracellular lipids [ 58 ], tumor grade-dependent increased de novo synthesis of fatty acids [ 59 ] and decrease in fatty acid beta-oxidation [ 60 , 61 , 62 ], and the pathognomonic accumulation of large intracellular lipid deposits [ 8 , 9 ]. Untargeted lipidomic analyses of ccRCC compared with normal kidney tissue revealed a characteristic “ccRCC lipidomic signature”, including increased levels of cholesteryl esters and triacylglycerols, as well as lower levels of phospholipids (other than phosphatidylcholines) and polyunsaturated fatty acids [ 63 , 64 ]. Furthermore, integrated lipidomic and transcriptomic analyses showed that alterations in cellular lipid composition in ccRCC were accompanied by multiple consistent changes in gene expression, including increased CD36 (fatty acid uptake), stearoyl-CoA desaturase and fatty acid elongases 2 and 5 (fatty acid synthesis), reduced carnitine palmitoyltransferase 1A (CPT1A, rate-limiting enzyme for the transport of fatty acids into mitochondria for beta-oxidation), as well as perilipin 2 (triglyceride storage in lipid droplets) [ 64 ].…”

“…Untargeted lipidomic analyses of ccRCC compared with normal kidney tissue revealed a characteristic “ccRCC lipidomic signature”, including increased levels of cholesteryl esters and triacylglycerols, as well as lower levels of phospholipids (other than phosphatidylcholines) and polyunsaturated fatty acids [ 63 , 64 ]. Furthermore, integrated lipidomic and transcriptomic analyses showed that alterations in cellular lipid composition in ccRCC were accompanied by multiple consistent changes in gene expression, including increased CD36 (fatty acid uptake), stearoyl-CoA desaturase and fatty acid elongases 2 and 5 (fatty acid synthesis), reduced carnitine palmitoyltransferase 1A (CPT1A, rate-limiting enzyme for the transport of fatty acids into mitochondria for beta-oxidation), as well as perilipin 2 (triglyceride storage in lipid droplets) [ 64 ]. These alterations likely play important roles in ccRCC biology, and are logical therapeutic targets for ongoing and future investigation.…”

Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma

“…This is accompanied by several transcriptomic events, some regulated by HIFs. Integrated lipidomic and transcriptomic analysis revealed increased accumulation of polyunsaturated fatty acids (PUFA) and overall fatty acid desaturation and elongation [82]. Interestingly, obesity is a risk factor in ccRCC, but paradoxically, patients with ccRCC who are obese have better prognosis [83][84][85].…”