2023/02/20
论文
论文标题：Slow TCA flux and ATP production in primary solid tumours but not metastases
作者：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, Gultekin, Yetis, Marishta, Argit, 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.
期刊：Nature
发表时间：2023/02/01
数字识别码：10.1038/s41586-022-05661-6
摘要：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.
