Piwnica-Worms, DavidBao, Gang2020-11-242021-12-012020-122020-11-06December 2Rao, Yi. "Hyperpolarized [1-13C]Pyruvate-to-[1-13C]Lactate Conversion is Rate Limited by Monocarboxylate Transporter-1 in the Plasma Membrane." (2020) Diss., Rice University. <a href="https://hdl.handle.net/1911/109583">https://hdl.handle.net/1911/109583</a>.https://hdl.handle.net/1911/109583Hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (MRSI) is a non-invasive metabolic imaging modality intended to inform the state of metabolic reprograming and carbon flux in tumors. Elevated hyperpolarized [1-13C]pyruvate-to-[1-13C]lactate conversion rates in aggressive tumors have been reported to be associated with enhanced glycolytic flux and lactate dehydrogenase A (LDHA) activity (Warburg effect). Herein, cross-sectional analysis using genetic and pharmacological tools in mechanistic studies applied to well-defined genetically-engineered cell lines and tumors demonstrated that initial hyperpolarized [1-13C]pyruvate-to-[1-13C]lactate conversion rates as well as global conversion were highly dependent on and critically rate-limited by the transmembrane influx of [1-13C]pyruvate mediated predominated by monocarboxylate transporter-1 (MCT1). Specifically, in a diffusion-unlimited cell-encapsulated alginate bead model, induced siRNA knockdown or overexpression of MCT1 quantitatively inhibited or enhanced, respectively, unidirectional pyruvate influxes and [1-13C]pyruvate-to-[1-13C]lactate conversion rates, independent of LDHA activity. Similarly, in tumor models in vivo, hyperpolarized [1-13C]pyruvate-to-[1-13C]lactate conversion was highly dependent on and critically rate-limited by the induced transmembrane influx of [1-13C]pyruvate mediated by MCT1. Furthermore, Kaplan–Meier survival analysis for patients with pancreatic, renal, lung and cervical cancers showed that high-level expression of MCT1 correlated with poor overall survival, and in selected tumors, MCT1 expression correlated with LDHA expression; thus, hyperpolarized [1-13C]pyruvate MRSI may provide a non-invasive functional assessment of MCT1 as a prognostic marker in select patient populations. Overall, hyperpolarized [1-13C]pyruvate MRSI primarily measures MCT1-mediated [1-13C]pyruvate transmembrane influx in vivo, not glycolytic flux or LDHA activity, driving a re-interpretation of this maturing new technology during clinical translation.application/pdfengCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.MCT1cancer metabolismhyperpolarized 13C13C magnetic resonance spectroscopynon-invasive biomarkersThesis2020-11-24