Tracer-based mapping of metabolic networks in vivo is a powerful approach for revealing metabolic reprogramming in human cancer. However, current in vivo labeling techniques for model animals face important challenges including insufficient depth of pathway coverage (e.g. inability to detect labeled nucleotides, proteins, and lipids) and stress-related artifacts. Here, we report stress-free administration of 13C6-glucose via liquid diet into mice. 13C enrichment was observed in metabolites of glycolysis, the Krebs cycle, the pentose phosphate pathway, nucleobases, UDP-sugars, as well as macromolecules glycogen, lipids, and proteins from major organs in NSG mice. We have applied the liquid diet method to map the glucose metabolic networks in NSCLC tumors in a patient-derived xenograft (PDX) model. We observed a high enrichment in the metabolites of glycolysis, Krebs cycle, and PPP as well as de novo synthesized nucleotides and amino acids by IC-UHR-FTMS analysis. Lung PDX displayed unexpected metabolic complexity, such as the use of pyruvate to fuel anaplerosis as well as gluconeogenesis. We also found high 13C enrichment in both tumor and plasma glutamine, which implies that glutamine in the PDX tumors largely came from other organs via the blood rather than being synthesized in situ. Our data showed that liquid diet is an effective and noninvasive means for comprehensive analysis of glucose-associated metabolic networks in human tumor xenografts, which can also be extended to SIRM studies with other fuel sources.
Acknowledgements: This work was supported in part by grants: 1R01ES022191-01 (to TWMF and RMH), 1P01CA163223-01A1 (to ANL and TWMF), and 1U24DK097215-01A1 (to RMH, TWMF, and ANL)
R.C. Sun was supported by a T32 training grant to M. Vore (5T32ES007266-25)
Citation Format: Ramon C. Sun, Marc O. Warmoes, Ye Yang, Pan Deng, Qiushi Sun, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan. Liquid diet introduction of tracers into mice for stable isotope-resolved metabolomics (SIRM) investigations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2502. doi:10.1158/1538-7445.AM2017-2502