Abstract LB-333: Metabolic imaging of cancer using nanostructure-initiator mass spectrometry

Abstract

Abstract Metabolic adaptation is critical for the development and progression of cancer, and may influence the sensitivity of tumor cells to chemotherapy. Tumor metabolic profiling provides insights into those processes, but most quantitative methods are relatively limited in terms of assay sensitivity and spatial resolution, and by necessity focus on cultured cells, explanted tumors, or tissue extracts. Nanostructure-initiator Mass Spectrometry (NIMS) is a mass-based imaging technique that requires no sample preparation or extraction, and provides unbiased characterization of tissue metabolites in situ at low micron resolution. Seeking mechanistic insights and biomarkers of drug response, we used NIMS to profile xenobiotic- and cell-intrinsic metabolism in cultured Burkitt's lymphoma cells and breast cancer xenograft tumors treated with Rapamycin (RAPA) and Docetaxel (DOC), respectively. In both systems, non-radioactive fluorothymidine (FLT) metabolism was monitored as an indicator of cell proliferation, since FLT phosphorylation by thymidine kinase occurs mainly in G1-S phase cells. Rapamycin, FLT, and phosphorylated FLT metabolites were readily detected in Raji cells. RAPA, a starvation mimetic, induced dramatic alterations in metabolome of Raji cells 30, 60, and 90 minutes after treatment. Significant changes in cellular energetic- and biosynthetic intermediates were seen, including elevations in D-glucose (p=0.071); stearic acid (p=0.089); uridine monophosphate (p=0.002); N-Acetyl-L-glutamic acid (p=0.033); tiglyglycine (p=0.011); and isobutyryl carnitine (p=0.037). NIMS analysis of tumor tissues and normal liver from SCID-Beige mice implanted with MDA-MB-231 tumors showed FLT metabolite distribution consistent with that expected for proliferating cells. DOC induced derangement in that distribution and in endogenous metabolite profiles when compared to vehicle treatment. NIMS metabolomics thus allows simultaneous quantification of drug exposure, drug metabolism, and broad metabolic responses to treatment with single cell resolution. Metabolic discrimination of tissues, as with NIMS, is increasingly used to inform our understanding of pathology and to identify endogenous biomarkers. The approach described here, where differences in xenobiotic metabolism are used as landmarks of proliferating tumor cells in situ, offers novel tools for translating in vitro findings into a deeper understanding of tumor responses to therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-333. doi:10.1158/1538-7445.AM2011-LB-333