期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：36
页码：22378-22389
DOI：10.1073/pnas.2003537117
出版社：The National Academy of Sciences of the United States of America
摘要：Hyperpolarized [1- 13 C]pyruvate magnetic resonance spectroscopic imaging (MRSI) is a noninvasive metabolic-imaging modality that probes carbon flux in tissues and infers the state of metabolic reprograming in tumors. Prevailing models attribute elevated hyperpolarized [1- 13 C]pyruvate-to-[1- 13 C]lactate conversion rates in aggressive tumors to enhanced glycolytic flux and lactate dehydrogenase A (LDHA) activity (Warburg effect). By contrast, we find by cross-sectional analysis using genetic and pharmacological tools in mechanistic studies applied to well-defined genetically engineered cell lines and tumors that initial hyperpolarized [1- 13 C]pyruvate-to-[1- 13 C]lactate conversion rates as well as global conversion were highly dependent on and critically rate-limited by the transmembrane influx of [1- 13 C]pyruvate mediated predominately by monocarboxylate transporter-1 (MCT1). Specifically, in a cell-encapsulated alginate bead model, induced short hairpin (shRNA) knockdown or overexpression of MCT1 quantitatively inhibited or enhanced, respectively, unidirectional pyruvate influxes and [1- 13 C]pyruvate-to-[1- 13 C]lactate conversion rates, independent of glycolysis or LDHA activity. Similarly, in tumor models in vivo, hyperpolarized [1- 13 C]pyruvate-to-[1- 13 C]lactate conversion was highly dependent on and critically rate-limited by the induced transmembrane influx of [1- 13 C]pyruvate mediated by MCT1. Thus, hyperpolarized [1- 13 C]pyruvate MRSI measures primarily MCT1-mediated [1- 13 C]pyruvate transmembrane influx in vivo, not glycolytic flux or LDHA activity, driving a reinterpretation of this maturing new technology during clinical translation. Indeed, 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 only in selected tumors, coincident with LDHA expression. Thus, hyperpolarized [1- 13 C]pyruvate MRSI provides a noninvasive functional assessment primarily of MCT1 as a clinical biomarker in relevant patient populations.
