Tobacco smoking induces metabolic reprogramming of renal cell carcinoma

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 MedvedovicDavid R. Plas, Julio A. Landero Figueroa, Jarek Meller, Maria F. Czyzyk-Krzeska

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Article numbere140522
Number of pages17
JournalJournal of Clinical Investigation
Volume131
Issue number1
Early online date24 Sept 2020
DOIs
Publication statusPublished - 04 Jan 2021
Externally publishedYes

Keywords

  • Carcinoma, Renal Cell/metabolism
  • Cellular Reprogramming
  • Female
  • Humans
  • Kidney Neoplasms/metabolism
  • Male
  • Tobacco Smoking/adverse effects

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