Glucose Indirectly Fuels the TCA Cycle in Tumors via Lactate Free

Circulating nutrients including glucose, amino acids, and intermediary metabolites, fuel metabolism and can be exchanged between normal and malignant cells and tissues. Glucose can be fully oxidized under aerobic conditions via the tricarboxylic acid (TCA) cycle, or it can be anaerobically catabolized via glycolysis to produce lactate. However, the role of circulating lactate as fuel in tumor and normal tissues has not been fully elucidated. To investigate the fluxes of circulating metabolites in mice, Hui and colleagues performed intravenous infusions of ¹³C-labeled nutrients. Circulatory turnover flux of lactate exceeded that of glucose, indicating that circulating glucose is not the predominant carbon source. The lactate was primarily derived from glucose, and ¹³C-labeled lactate catabolism contributed to labeled TCA cycle intermediates in all tissues. In fasted mice, glucose primarily contributed to TCA cycle metabolism indirectly via circulating lactate, except in the brain where the TCA cycle was predominantly fueled directly by glucose. The concentration of circulating glucose was higher in fed mice, but in most tissues glucose still labeled TCA intermediates through circulating lactate. The brain utilized glucose directly, and the muscle and heart used circulating glucose and lactate at approximately the same rate to fuel the TCA cycle. In tumors, circulating lactate primarily fueled the TCA cycle in mouse models of lung and pancreatic cancers, with circulating lactate exceeding the contribution of glucose to the TCA cycle by approximately 2-fold. In the lung tumors, as in normal lung tissue, lactate was the largest contributor to the TCA cycle. In contrast, glutamine was the primary TCA fuel in pancreatic tumors and normal pancreas, suggesting that the preference for tumor TCA substrates mirrors the tissue of origin. Altogether, these findings reveal an uncoupling of glycolysis and the TCA cycle, with circulating lactate serving as the primary TCA cycle substrate in normal tissues and tumors.

Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, et al. Glucose feeds the TCA cycle via circulating lactate. Nature 2017;551:115–8.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.