High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non–Small Cell Lung Cancer in Patients

In patients with non–small cell lung cancer (NSCLC), the relationship between tumor metabolism and clinical outcomes is unknown. Here,¹³C-labeled nutrients were intraoperatively infused into more than 90 patients with surgically resectable pulmonary lesions, and metabolic properties of resected tumors were correlated with survival. In NSCLCs infused with 1₃ C-glucose, high¹³C enrichment in tricarboxylic acid (TCA) cycle intermediates conferred a HR of 3.8 for early death, typically with metastasis. To test whether these features reflect requirements for metastasis, we generated patient-derived xenografts that spontaneously metastasize to multiple organs. Treatment with an electron transport chain (ETC) inhibitor reduced glucose-derived TCA cycle labeling but did not suppress subcutaneous tumor growth. However, ETC blockade reduced the abundance of circulating cancer cells and suppressed xenograft metastatic burden in distant organs. Our data demonstrate that isotope labeling can identify metabolic properties associated with metastasis in patients and that blocking the ETC suppresses metastasis in mice. Significance: Intraoperative¹³C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.