Abstract 2501: Assessing metabolic activity of patient-derived models of non-small cell lung cancer using stable isotope resolved metabolomics (SIRM)

Abstract

Abstract Stable Isotope-Resolved Metabolomics (SIRM) has been a useful tool in interrogating metabolic reprogramming in cancer. We have recently published several protocols using SIRM in patient-derived models of non-small cell lung cancer (NSCLC)1. In this case study, we compared central metabolic activity in three different model systems, all derived from the same patient. Slices from the human tumor (Warburg slices 2,3), slices from an NSG mouse bearing the human tumor 4, and the patient-derived cell culture were incubated in [U-13C]-glucose or [U-13C,15N]-glutamine for 24 hours. Samples were then harvested and analyzed by gas-chromatography-mass spectrometry and NMR. All three models displayed similar levels of fractional enrichment after 24 hours, making metabolic comparison possible, despite their very different 3D architectures. Glucose metabolism in particular, showed consistent labeling patterns of metabolites in glycolysis and the Krebs cycle. Glutamine metabolism, however, was distinct in the cell culture, with a pattern that indicated upregulation of anaplerotic glutaminolysis. Activation of glutaminolysis may be an important transformative step in the establishment of a viable cell culture. We are also in the process of validating the present finding by comparing multiple patient-derived models of NSCLC and tracking the evolution of their metabolic activity. 1 Lane, A. N., Higashi, R. M. & Fan, T. W.-M. Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM) Metabolomics 12, 1-15 (2016). 2 Fan, T. W.-M. et al. Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator β-glucan in a two-case ex vivo non-small cell lung cancer study. CSH Molec. Case Studies J. 2, a00083, (2016). 3 Fan, T. W.-M., Lane, A. N. & Higashi, R. M. Stable Isotope Resolved Metabolomics Studies in ex vivo Tissue Slices. Bio-protocol 6, e1730 (2016). 4 Lane, A. N., Yan, J. & Fan, T. W.-M. 13C Tracer Studies of Metabolism in Mouse Tumor Xenografts. Bio-protocol 5, e1650 (2015). Citation Format: Connor J. Kinslow, Jinlian Tan, Yihua Cai, Jun Yan, Richard M. Higashi, Andrew N. Lane, Teresa W. Fan. Assessing metabolic activity of patient-derived models of non-small cell lung cancer using stable isotope resolved metabolomics (SIRM) [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 2501. doi:10.1158/1538-7445.AM2017-2501