An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma

Abstract

Summary Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism and anti-oxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (“metabolograms”) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which correspond to a poor-survival subgroup in the ccRCC TCGA cohort.

Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative Dixon MRI

“…Interestingly, we found a significant increase in the carbohydrate pathway metabolites (glucose 6-phosphate [G6P], and galactose 1-phosphate (Gal1P) and redox markers (glutathione [GSH] and glutathione disulfide [GSSG]), which are consistent with prior metabolic analysis reported on ccRCC tumors (35)(36)(37).…”

“…ccRCC is characterized by significant alterations in intermediary metabolism and antioxidant response, and metabolite increases in glutathione and cysteine/methionine metabolic pathways are associated with tumor progression and metastasis (35,36). In order to understand the correlation between FF and cellular metabolism in these tumors, we performed a targeted metabolomic analysis of ccRCC, from fresh frozen high-quality tumor samples and corresponding adjacent URP.…”

Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging

“…Glutathione (GSH) is considered the predominant endogenous cellular antioxidant, playing a critical role in the cellular defensive response to oxidative stress by neutralizing free radicals and reactive oxygen species(21). In ccRCC in particular, the conditionally essential amino acid glutamine is subjected to reductive carboxylation leading to production of the oncometabolite 2HG(22) as well as being a precursor for the major antioxidant system comprised of GSH and GSSG(19,23); indeed, a recent study showed that metabolites that eventually contribute to GSH biosynthesis were able to significantly separate ccRCC tumors from normal tissues(24), emphasizing the importance of this metabolic pathway to ccRCC.…”

Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth

“…Based on work from our group and others (2, 3), it is becoming evident that RCC is truly a metabolic disease such that exploitation of newly discovered altered metabolic pathways is a fertile area for therapeutic target discovery. In our continuing evaluation of such reprogramming, it has become apparent that two such pathways, PAK4/β-catenin and NAD synthesis, are important in RCC progression but as yet have not been evaluated with respect to potential therapeutic targeting in this disease.…”