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Slow TCA flux and ATP production in primary solid tumours but not metastases
Open accessAbstract
Tissues derive ATP from two pathways-glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism 1. In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras-mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect 2,3), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue's major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.
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“Intriguingly, a recent study determined that “bulk” fermentative and respiratory rates in primary tumors are lower than previously postulated,4”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [4]
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Metadata
- Authors
- Bartman, C. R., Weilandt, D. R., Shen, Y., Lee, W. D., Han, Y., TeSlaa, T., Jankowski, C. S. R., Samarah, L., Park, N. R., da Silva-Diz, V., Aleksandrova, M., Gultekin, Y., Marishta, A., Wang, L., Yang, L., Roichman, A., Bhatt, V., Lan, T., Hu, Z., Xing, X., Lu, W., Davidson, S., Wühr, M., Vander Heiden, M. G., Herranz, D., Guo, J. Y., Kang, Y., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- University of California, Los Angeles (US)
- Rutgers, The State University of New Jersey (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Rabinowitz, Joshua D.
- ORCID
- Bartman, Caroline R.
- Weilandt, Daniel R.
- Shen, Yihui
- Lee, Won Dong
- Han, Yujiao
- TeSlaa, Tara
- Jankowski, Connor S. R.
- Samarah, Laith
- Park, Noel R.
- da Silva-Diz, Victoria
- Aleksandrova, Maya
- Wang, Lin
- Yang, Lifeng
- Roichman, Asael
- Bhatt, Vrushank
- Lan, Taijin
- Hu, Zhixian
- Xing, Xi
- Lu, Wenyun
- Davidson, Shawn
- Wühr, Martin
- Vander Heiden, Matthew G.
- Herranz, Daniel
- Guo, Jessie Yanxiang
- Kang, Yibin
- Rabinowitz, Joshua D.
- Venue
- Nature
- Published
- 2023-02-01
- Volume
- 614
- Issue
- 7947
- Pages
- 349-357
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10288502
- OpenAlex
- W4318771331
- Cited by
- 299
- References
- 83
- Citations by year
- 2026: 49 · 2025: 93 · 2024: 97 · 2023: 60
- FWCI
- 38.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- Leukemia and Lymphoma Society (1386-23)
- Ludwig Institute for Cancer Research
- National Institutes of Health
- Stand Up To Cancer (SU2C-AACR-DT-20-16, T32GM007388)
- National Cancer Institute (R01CA236936, K99CA273517, P30CA072720, R01CA237347, R50CA211437, R35CA242379, R01CA163591)
- National Institute of General Medical Sciences (T32GM007388, R35GM128813)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK127843, DP1DK113643)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- TCA cycle, glycolysis, ATP production, cancer metabolism, Warburg effect, lung metastasis, breast cancer, pancreatic cancer, leukemia, tracer infusion, energy metabolism, protein synthesis
- MeSH terms
- Adenosine Triphosphate, Animals, Breast Neoplasms, Citric Acid Cycle, Deceleration, Energy Metabolism, Glycolysis, Lung Neoplasms, Neoplasm Metastasis, Organ Specificity, Pancreatic Neoplasms, Protein Biosynthesis, Proto-Oncogene Proteins p21(ras), Mice
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