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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a 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) 13C MRS of pyruvate to lactate conversion and ex vivo 1H 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 13C pyruvate to lactate after intravenous injection interrogating upregulated lactate dehydrogenase (LDH) activity in aggressive PDXs. Total ex vivo lactate measurement by 1H NMR spectroscopy showed a direct correlation with in vivo dynamic pyruvate-to-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-1α) 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.

• Authors: Prasanta Dutta, Mayrim R Perez, Jaehyuk Lee, Yaan Kang, Michael Pratt, Travis C Salzillo, Joseph Weygand, Niki M Zacharias, Seth T Gammon, Eugene J Koay, Michael Kim, Florencia McAllister, Subrata Sen, Anirban Maitra, David Piwnica-Worms, Jason B Fleming, Pratip K Bhattacharya
• Journal: Journal of proteome research (J Proteome Res) Vol. 18 Issue 7 Pg. 2826-2834 (07 05 2019) ISSN: 1535-3907 [Electronic] United States
• PMID: 31120258 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lactic Acid
• Pyruvic Acid
• L-Lactate Dehydrogenase

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Carcinoma, Pancreatic Ductal
• Glycolysis
• Heterografts
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Lactic Acid (metabolism)
• Magnetic Resonance Imaging (methods)
• Magnetic Resonance Spectroscopy (methods)
• Pancreatic Neoplasms (diagnosis, metabolism)
• Pyruvic Acid (metabolism)