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Mitochondrial complex I promotes kidney cancer metastasis.
Bezwada, Divya; Perelli, Luigi; Lesner, Nicholas P; Cai, Ling; Brooks, Bailey; Wu, Zheng; Vu, Hieu S; Sondhi, Varun; Cassidy, Daniel L; Kasitinon, Stacy; Kelekar, Sherwin; Cai, Feng; Aurora, Arin B; Patrick, McKenzie; Leach, Ashley; Ghandour, Rashed; Zhang, Yuanyuan; Do, Duyen; McDaniel, Phyllis; Sudderth, Jessica; Dumesnil, Dennis; House, Sara; Rosales, Tracy; Poole, Alan M; Lotan, Yair; Woldu, Solomon; Bagrodia, Aditya; Meng, Xiaosong; Cadeddu, Jeffrey A; Mishra, Prashant; Garcia-Bermudez, Javier; Pedrosa, Ivan; Kapur, Payal; Courtney, Kevin D; Malloy, Craig R; Genovese, Giannicola; Margulis, Vitaly; DeBerardinis, Ralph J.
Affiliation
  • Bezwada D; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Perelli L; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lesner NP; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Cai L; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Brooks B; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Wu Z; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Vu HS; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Sondhi V; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Cassidy DL; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Kasitinon S; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Kelekar S; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Cai F; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Aurora AB; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Patrick M; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Leach A; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Ghandour R; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Zhang Y; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Do D; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • McDaniel P; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Sudderth J; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Dumesnil D; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • House S; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Rosales T; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Poole AM; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Lotan Y; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Woldu S; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Bagrodia A; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Meng X; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Cadeddu JA; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Mishra P; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Garcia-Bermudez J; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Pedrosa I; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Kapur P; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Courtney KD; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Malloy CR; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Genovese G; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Margulis V; Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • DeBerardinis RJ; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature ; 633(8031): 923-931, 2024 Sep.
Article in En | MEDLINE | ID: mdl-39143213
ABSTRACT
Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Renal Cell / Citric Acid Cycle / Electron Transport Complex I / Kidney Neoplasms / Mitochondria / Neoplasm Metastasis Limits: Animals / Female / Humans / Male Language: En Journal: Nature Year: 2024 Document type: Article Affiliation country: United States Country of publication: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Renal Cell / Citric Acid Cycle / Electron Transport Complex I / Kidney Neoplasms / Mitochondria / Neoplasm Metastasis Limits: Animals / Female / Humans / Male Language: En Journal: Nature Year: 2024 Document type: Article Affiliation country: United States Country of publication: United kingdom