TY - JOUR
T1 - Hyperpolarized [1-13C]pyruvate-to-[1-13C]lactate conversion is rate-limited by monocarboxylate transporter-1 in the plasma membrane
AU - Rao, Yi
AU - Gammon, Seth
AU - Zacharias, Niki M.
AU - Liu, Tracy
AU - Salzillo, Travis
AU - Xi, Yuanxin
AU - Wang, Jing
AU - Bhattacharya, Pratip
AU - Piwnica-Worms, David
N1 - Funding Information:
This study was funded by NIH Grant P50 CA94056 to the MD Anderson Cancer Center-Washington University Inter-Institutional Molecular Imaging Center; the Gerald Dewey Dodd, Jr., Endowed Distinguished Chair of the University of Texas MD Anderson Cancer Center; a faculty University of Texas Science and Technology Acquisition and Retention Award; a grant from the Pancreatic Cancer Action Network (16-65-BHAT); Cancer Prevention and Research Institute of Texas Research Training Grant Award RP170067; and a generous gift from the Estate of Barbara Cox Anthony/Koch Foundation. We thank the Biostatistics Resource and the Small Animal Imaging Facility of the MD Anderson Cancer Center for animal imaging assistance, especially Charles Kingsley, Jorge Delacerda, Jim Bankson, Gary Martinez, and Christopher Walker. The Biostatistics Resource and the Small Animal Imaging Facility obtain support from NCI Cancer Center Support Grant P30 CA016672.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/9/8
Y1 - 2020/9/8
N2 - Hyperpolarized [1-13C]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 [1-13C]pyruvate-to-[1-13C]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 [1-13C]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 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 [1-13C]pyruvate-to-[1-13C]lactate conversion rates, independent of glycolysis or 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. Thus, hyperpolarized [1-13C]pyruvate MRSI measures primarily MCT1-mediated [1-13C]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 [1-13C]pyruvate MRSI provides a noninvasive functional assessment primarily of MCT1 as a clinical biomarker in relevant patient populations.
AB - Hyperpolarized [1-13C]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 [1-13C]pyruvate-to-[1-13C]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 [1-13C]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 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 [1-13C]pyruvate-to-[1-13C]lactate conversion rates, independent of glycolysis or 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. Thus, hyperpolarized [1-13C]pyruvate MRSI measures primarily MCT1-mediated [1-13C]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 [1-13C]pyruvate MRSI provides a noninvasive functional assessment primarily of MCT1 as a clinical biomarker in relevant patient populations.
KW - Hyperpolarized NMR
KW - Imaging biomarker
KW - MCT1
KW - Monocarboxylate transporters
KW - [1-C]pyruvate
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U2 - 10.1073/pnas.2003537117
DO - 10.1073/pnas.2003537117
M3 - Article
C2 - 32839325
AN - SCOPUS:85090614239
SN - 0027-8424
VL - 117
SP - 22378
EP - 22389
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -