Fig. 3

A PDTX model of NSCLC shows attenuated glycolysis and enhanced malic enzyme activity and use of non-Krebs cycle-derived αKG for Glu/GSH synthesis relative to the corresponding ex vivo tissue culture model. Mice bearing F0 PDTX (n = 3) from patient UK025 were fed the ¹³C₆-Glc enriched liquid diet for 18 h (cf. Fig. 1) before necropsy. Tumor tissues were dissected, weighed, and flash-frozen in liquid N₂. The freshly thin-sliced UK025 tumor tissues were cultured ex vivo in ¹³C₆-glucose for 24 h before flash-frozen in liquid N₂. Both sets of tissues were processed and analyzed by IC-UHR-FTMS as described in Methods. a Tracing of glucose carbon through glycolysis, gluconeogenesis (GNG), the Krebs cycle, malic enzyme (ME) reactions, and synthesis of Glu/GSH. Not all possible labeled metabolites are shown. Black circle: ¹²C; red circle, green circle: ¹³C from pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PCB)-initiated Krebs cycle reactions, respectively; pink circle: ¹³C derived from ME reaction; PEPCK: PEP carboxykinase. b-i fractional enrichments in the isotopologues of phosphoenolpyruvate (PEP), citrate, α-ketoglutarate (αKG), succinate, malate, Glu, reduced glutathione (GSH), and Asp, respectively. The x-axis denotes the number of ¹³C atoms present in each compound. Values shown are mean ± SEM (n = 3). ^* 0.01 < P < 0.05; ^** 0.001 < P < 0.01; ^*** P < 0.001, two-tailed t-test (see Methods)