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 da Silva-Diz, Maya Aleksandrova, Yetis Gultekin, Argit Marishta, Lin Wang, Lifeng Yang, Asael Roichman, Vrushank Bhatt, Taijin Lan, Zhixian Hu, Xi XingWenyun Lu, Shawn Davidson, Martin Wühr, Matthew G. Vander Heiden, Daniel Herranz, Jessie Yanxiang Guo, Yibin Kang, Joshua D. Rabinowitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)349-357
Number of pages9
JournalNature
Volume614
Issue number7947
DOIs
StatePublished - Feb 9 2023

ASJC Scopus subject areas

  • General

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