Tobacco smoking induces metabolic reprogramming of renal cell carcinoma
James Reigle, … , Jarek Meller, Maria F. Czyzyk-Krzeska
James Reigle, … , Jarek Meller, Maria F. Czyzyk-Krzeska
Published September 24, 2020
Citation Information: J Clin Invest. 2021;131(1):e140522. https://doi.org/10.1172/JCI140522.
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Clinical Research and Public Health Metabolism Oncology

Tobacco smoking induces metabolic reprogramming of renal cell carcinoma

Abstract

BACKGROUND Clear 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.METHODS We 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).RESULTS All 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.CONCLUSION The 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.FUNDING Department of Defense, Veteran Administration, NIH, ACS, and University of Cincinnati Cancer Institute.

Authors

James Reigle, Dina Secic, Jacek Biesiada, Collin Wetzel, Behrouz Shamsaei, Johnson Chu, Yuanwei Zang, Xiang Zhang, Nicholas J. Talbot, Megan E. Bischoff, Yongzhen Zhang, Charuhas V. Thakar, Krishnanath Gaitonde, Abhinav Sidana, Hai Bui, John T. Cunningham, Qing Zhang, Laura S. Schmidt, W. Marston Linehan, Mario Medvedovic, David R. Plas, Julio A. Landero Figueroa, Jarek Meller, Maria F. Czyzyk-Krzeska

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Figure 2

Metabolic profiling of ccRCCs and NKTs from LTS and NS.

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Metabolic profiling of ccRCCs and NKTs from LTS and NS. (A) Volcano plot...
(A) Volcano plot shows metabolites with differential abundance (P < 0.05, fold change, Wilcoxon nonparametric test) between all NKTs (n = 36) and all ccRCCs (n = 37). Differentially abundant metabolites are labeled by numbers (see Supplemental Table 5B for the identification of the indicated metabolites). Intermediates of the Warburg effect labeled in brown. (B) Volcano plots show metabolites with differential abundance in NKTs from LTS compared with NS. (C) Volcano plots show metabolites with differential abundance in ccRCCs from LTS compared with NS. (D) Pathway for metabolism of phenylacetylglutamine (PAGln). (E) Pathway of OPH and GSH biosynthesis.