TY - JOUR
T1 - Tobacco smoking induces metabolic reprogramming of renal cell carcinoma
AU - Reigle, James
AU - Secic, Dina
AU - Biesiada, Jacek
AU - Wetzel, Collin
AU - Shamsaei, Behrouz
AU - Chu, Johnson
AU - Zang, Yuanwei
AU - Zhang, Xiang
AU - Talbot, Nicholas J.
AU - Bischoff, Megan E.
AU - Zhang, Yongzhen
AU - Thakar, Charuhas V.
AU - Gaitonde, Krishnanath
AU - Sidana, Abhinav
AU - Bui, Hai
AU - Cunningham, John T.
AU - Zhang, Qing
AU - Schmidt, Laura S.
AU - Linehan, W. Marston
AU - Medvedovic, Mario
AU - Plas, David R.
AU - Figueroa, Julio A.Landero
AU - Meller, Jarek
AU - Czyzyk-Krzeska, Maria F.
N1 - Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI140522
DO - 10.1172/JCI140522
M3 - Article
C2 - 32970633
AN - SCOPUS:85098884280
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - e140522
ER -