Combining Hyperpolarized Real-Time Metabolic Imaging and NMR Spectroscopy To Identify Metabolic Biomarkers in Pancreatic Cancer

被引：31

作者：

Dutta, Prasanta ^{[1
]}

Perez, Mayrim R. ^{[2
]}

Lee, Jaehyuk ^{[1
]}

Kang, Yaan ^{[2
]}

Pratt, Michael ^{[2
]}

Salzillo, Travis C. ^{[1
]}

Weygand, Joseph ^{[1
]}

Zacharias, Niki M. ^{[1
,3
]}

Gammon, Seth T. ^{[1
]}

Koay, Eugene J. ^{[3
]}

Kim, Michael ^{[2
]}

McAllister, Florencia ^{[4
]}

Sen, Subrata ^{[5
]}

Maitra, Anirban ^{[6
]}

Piwnica-Worms, David ^{[1
]}

Fleming, Jason B. ^{[2
,7
]}

Bhattacharya, Pratip K. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[7] H Lee Moffitt Canc Ctr & Res Inst, Dept Gastrointestinal Oncol, Tampa, FL 33612 USA

来源：

JOURNAL OF PROTEOME RESEARCH | 2019年 / 18卷 / 07期

基金：

美国国家卫生研究院;

关键词：

hyperpolarized metabolic imaging; NMR spectroscopy patient derived xenograft (PDX); pancreatic cancer; tumor metabolism; NMR metabolomics; LDH-A; LACTATE-DEHYDROGENASE; IN-VIVO; TUMOR METABOLISM; EARLY RESPONSE; INHIBITION; MYC; PATHWAY; BIOLOGY; GROWTH;

D O I：

10.1021/acs.jproteome.9b00132

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Pancreatic ductal adenocarcinoma (PDAC) is a 120 deadly cancer that progresses without any symptom, and oftentimes, it is detected at an advanced stage. The lack of prior symptoms and effective treatments have created a knowledge gap in the management of this lethal disease. This issue can be addressed by developing novel noninvasive imaging-based biomarkers in PDAC. We explored in vivo hyperpolarized (HP)C- 13 MRS of pyruvate to lactate conversion and ex vivo H-1 NMR spectroscopy in a panel of well-annotated patient-derived PDAC xenograft (PDXs) model and investigated the correlation between aberrant glycolytic metabolism and aggressiveness of the tumor. Real-time metabolic imaging data demonstrate the immediate intracellular conversion of HP C-13 pyruvate to lactate after intravenous injection interrogating upregulated lactate dehydrogenase (LDH) activity in aggressive PDXs. Total ex vivo lactate measurement by H-1 NMR spectroscopy showed a direct correlation with in vivo dynamic pyruvateto-lactate conversion and demonstrated the potential of dynamic metabolic flux as a biomarker of total lactate concentration and aggressiveness of the tumor. Furthermore, the metabolite concentrations were very distinct among all four tumor types analyzed in this study. Overexpression of LDH-A and hypoxia-inducible factor (HIF-1 alpha) plays a significant role in the conversion kinetics of HP pyruvate-to-lactate in tumors. Collectively, these data identified aberrant metabolic characteristics of pancreatic cancer PDXs and could potentially delineate metabolic targets for therapeutic intervention. Metabolic imaging with HP pyruvate and NMR metabolomics may enable identification and classification of aggressive subtypes of patient-derived xenografts. Translation of this real-time metabolic technique to the clinic may have the potential to improve the management of patients at high risk of developing pancreatic diseases.

引用

页码：2826 / 2834

页数：9

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