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Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

ABSTRACT: BACKGROUNDClear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinctive metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC, with unknown effects on tumor pathobiology.METHODSWe investigated the landscape of ccRCCs and paired normal kidney tissues using integrated transcriptomic, metabolomic, and metallomic approaches in a cohort of white males who were long-term current smokers (LTS) or were never smokers (NS).RESULTSAll 3 Omics domains consistently identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OXPHOS) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine, and histidine. Cadmium, copper, and inorganic arsenic accumulated in LTS tumors, showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. A gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas ccRCC tumors that was independent of genomic alterations.CONCLUSIONThe work identified the TS-related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provided rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OXPHOS status. The metallomic analysis revealed the role of disrupted metal homeostasis in ccRCC, highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.FUNDINGDepartment of Defense, Veteran Administration, NIH, ACS, and University of Cincinnati Cancer Institute.

SUBMITTER: Reigle J

PROVIDER: S-EPMC7773408 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Head and neck squamous cell carcinoma (HNSCC) is comprised of metabolically linked distinct compartments. Cancer-associated fibroblasts (CAF) and nonproliferative carcinoma cells display a glycolytic metabolism, while proliferative carcinoma cells rely on mitochondrial oxidative metabolism fueled by the catabolites provided by the adjacent CAFs. Metabolic coupling between these reprogrammed compartments contributes to HNSCC aggressiveness. In this study, we examined the effects of cigarette smoke-exposed CAFs on metabolic coupling and tumor aggressiveness of HNSCC. Cigarette smoke (CS) extract was generated by dissolving cigarette smoke in growth media. Fibroblasts were cultured in CS or control media. HNSCC cells were cocultured in vitro and coinjected in vivo with CS or control fibroblasts. We found that CS induced oxidative stress, glycolytic flux and MCT4 expression, and senescence in fibroblasts. MCT4 upregulation was critical for fibroblast viability under CS conditions. The effects of CS on fibroblasts were abrogated by antioxidant treatment. Coculture of carcinoma cells with CS fibroblasts induced metabolic coupling with upregulation of the marker of glycolysis MCT4 in fibroblasts and markers of mitochondrial metabolism MCT1 and TOMM20 in carcinoma cells. CS fibroblasts increased CCL2 expression and macrophage migration. Coculture with CS fibroblasts also increased two features of carcinoma cell aggressiveness: resistance to cell death and enhanced cell migration. Coinjection of carcinoma cells with CS fibroblasts generated larger tumors with reduced apoptosis than control coinjections, and upregulation of MCT4 by CS exposure was a driver of these effects. We demonstrate that a tumor microenvironment exposed to CS is sufficient to modulate metabolism and cancer aggressiveness in HNSCC. IMPLICATIONS: CS shifts cancer stroma toward glycolysis and induces head and neck cancer aggressiveness with a mitochondrial profile linked by catabolite transporters and oxidative stress. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/17/9/1893/F1.large.jpg.

Project description:Fumarate hydratase (FH)-deficient kidney cancer undergoes metabolic remodeling, with changes in mitochondrial respiration, glucose, and glutamine metabolism. These changes represent multiple biochemical adaptations in glucose and fatty acid metabolism that supports malignant proliferation. However, the metabolic linkages between altered mitochondrial function, nucleotide biosynthesis and NADPH production required for proliferation and survival have not been elucidated. To characterize the alterations in glycolysis, the Krebs cycle and the pentose phosphate pathways (PPP) that either generate NADPH (oxidative) or do not (non-oxidative), we utilized [U-(13)C]-glucose, [U-(13)C,(15)N]-glutamine, and [1,2- (13)C2]-glucose tracers with mass spectrometry and NMR detection to track these pathways, and measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of growing cell lines. This metabolic reprogramming in the FH null cells was compared to cells in which FH has been restored. The FH null cells showed a substantial metabolic reorganization of their intracellular metabolic fluxes to fulfill their high ATP demand, as observed by a high rate of glucose uptake, increased glucose turnover via glycolysis, high production of glucose-derived lactate, and low entry of glucose carbon into the Krebs cycle. Despite the truncation of the Krebs cycle associated with inactivation of fumarate hydratase, there was a small but persistent level of mitochondrial respiration, which was coupled to ATP production from oxidation of glutamine-derived ?-ketoglutarate through to fumarate. [1,2- (13)C2]-glucose tracer experiments demonstrated that the oxidative branch of PPP initiated by glucose-6-phosphate dehydrogenase activity is preferentially utilized for ribose production (56-66%) that produces increased amounts of ribose necessary for growth and NADPH. Increased NADPH is required to drive reductive carboxylation of ?-ketoglutarate and fatty acid synthesis for rapid proliferation and is essential for defense against increased oxidative stress. This increased NADPH producing PPP activity was shown to be a strong consistent feature in both fumarate hydratase deficient tumors and cell line models.

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Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

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