Slow TCA flux and ATP production in primary solid tumours but not metastases

Caroline R. Bartman, Daniel R. Weilandt, Yihui Shen, Won Dong Lee, Yujiao Han, Tara TeSlaa, Connor S. R. Jankowski, Laith Samarah, Noel R. Park, Victoria Silva-Diz, Maya Aleksandrova, Yetis Gultekin, Argit Marishta, Lin Wang, Lifeng Yang, Asael Roichman, Vrushank Bhatt, Taijin Lan, Zhixian Hu, Xi Xing, Wenyun Lu, Shawn Davidson, Martin Wühr, Matthew G. Vander Heiden, Daniel Herranz, Jessie Yanxiang Guo, Yibin Kang and Joshua D. Rabinowitz ()
Additional contact information
Caroline R. Bartman: Princeton University
Daniel R. Weilandt: Princeton University
Yihui Shen: Princeton University
Won Dong Lee: Princeton University
Yujiao Han: Princeton University
Tara TeSlaa: Princeton University
Connor S. R. Jankowski: Princeton University
Laith Samarah: Princeton University
Noel R. Park: Princeton University
Victoria Silva-Diz: Rutgers University
Maya Aleksandrova: Rutgers University
Yetis Gultekin: Massachusetts Institute of Technology
Argit Marishta: Princeton University
Lin Wang: Princeton University
Lifeng Yang: Princeton University
Asael Roichman: Princeton University
Vrushank Bhatt: Rutgers University
Taijin Lan: Rutgers University
Zhixian Hu: Rutgers University
Xi Xing: Princeton University
Wenyun Lu: Princeton University
Shawn Davidson: Princeton University
Martin Wühr: Princeton University
Matthew G. Vander Heiden: Massachusetts Institute of Technology
Daniel Herranz: Rutgers University
Jessie Yanxiang Guo: Rutgers University
Yibin Kang: Princeton University
Joshua D. Rabinowitz: Princeton University

Nature, 2023, vol. 614, issue 7947, 349-357

Abstract: Abstract 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 metabolism1. 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 effect2,3), 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.

Date: 2023
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DOI: 10.1038/s41586-022-05661-6

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