Journal Article

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

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

2023

Overview

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. As solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/45/320 / 631/67/2327 / Adenosine Triphosphate - biosynthesis / Adenosine Triphosphate - metabolism / Animals / Breast cancer / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Carbon / Citric Acid Cycle - physiology / Deceleration / Dehydrogenases / Electron transport / Electron transport chain / Energy costs / Energy Metabolism / Fatty acids / Fluctuations / Glucose / Glycolysis / Humanities and Social Sciences / Labeling / Leukemia / Lung cancer / Lung Neoplasms - metabolism / Lung Neoplasms - secondary / Metabolism / Metabolites / Metastases / Metastasis / Mice / Mitochondrial DNA / multidisciplinary / Muscle contraction / Neoplasm Metastasis / Organ Specificity / Pancreatic cancer / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Protein Biosynthesis / Protein synthesis / Science / Science (multidisciplinary) / Solid tumors / Tissues / Tracers / Tricarboxylic acid cycle / Tumors