Hyperpolarized [1-13C]Pyruvate-to-[1-13C]Lactate Conversion is Rate Limited by Monocarboxylate Transporter-1 in the Plasma Membrane

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dc.contributor.advisorPiwnica-Worms, Daviden_US
dc.contributor.advisorBao, Gangen_US
dc.creatorRao, Yien_US
dc.date.accessioned2020-11-24T14:29:40Zen_US
dc.date.available2021-12-01T06:01:10Zen_US
dc.date.created2020-12en_US
dc.date.issued2020-11-06en_US
dc.date.submittedDecember 2020en_US
dc.date.updated2020-11-24T14:29:41Zen_US
dc.description.abstractHyperpolarized [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.en_US
dc.embargo.terms2021-12-01en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationRao, 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>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/109583en_US
dc.language.isoengen_US
dc.rightsCopyright 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.en_US
dc.subjectMCT1en_US
dc.subjectcancer metabolismen_US
dc.subjecthyperpolarized 13Cen_US
dc.subject13C magnetic resonance spectroscopyen_US
dc.subjectnon-invasive biomarkersen_US
dc.titleHyperpolarized [1-13C]Pyruvate-to-[1-13C]Lactate Conversion is Rate Limited by Monocarboxylate Transporter-1 in the Plasma Membraneen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBioengineeringen_US
thesis.degree.disciplineEngineeringen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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