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 1

Identification of genes differentially regulated by TS in ccRCCs.

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Identification of genes differentially regulated by TS in ccRCCs. (A) He...
(A) Heatmap of all differentially regulated genes shows stratification with TS (marked by black in the top bar). Pink bar represents tumor grades, and yellow bar represents mutations in VHL (WT: wild type, PM: point mutations, FS: frameshift mutations). Dark blue marks in the bar on the right of the heatmap indicate mitochondrial genes induced in the ccRCCs from LTS. (B) ROC curves for the classification of the samples into classes defined by TS (magenta), tumor grade (blue), or VHL mutation status (cyan). Random classifier is drawn as a diagonal gray line, and classification accuracy is represented by the AUC indicating that observed clustering provides the best classification for TS status. (C) Box-whisker plots for expression of mitochondrial genes in ccRCCs from NS and LTS. The boxes represent lower and upper quartiles separated by the median (thick horizontal line) and the whiskers extend to the minimum and maximum values, excluding points that are outside the 1.5 IQR from the box (marked as circles). P values from Mann-Whitney-Wilcoxon test are provided at the top. (D) Model showing localization of the 18 induced genes (marked in red) in the context of mitochondrial electron transport chain. ccRCCs from 15 NS and 19 LTS were analyzed.