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Quantitative Metabolomics and Lipoprotein Analysis of PDAC Patients Suggests Serum Marker Categories for Pancreatic Function, Pancreatectomy, Cancer Metabolism, and Systemic Disturbances

  • Gyuntae Bae
    Gyuntae Bae
    Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Tübingen 72076, Germany
    Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen 72076, Germany
    More by Gyuntae Bae
  • Georgy Berezhnoy
    Georgy Berezhnoy
    Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Tübingen 72076, Germany
  • Alejandra Flores
    Alejandra Flores
    Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Tübingen 72076, Germany
  • Claire Cannet
    Claire Cannet
    Bruker BioSpin GmbH & Co. KG, BioPharma and Applied Division, Ettlingen 76275, Germany
  • Hartmut Schäfer
    Hartmut Schäfer
    Bruker BioSpin GmbH & Co. KG, BioPharma and Applied Division, Ettlingen 76275, Germany
  • Marc H. Dahlke
    Marc H. Dahlke
    Department of General and Visceral Surgery, Robert-Bosch-Krankenhaus, Stuttgart 70376, Germany
  • Patrick Michl
    Patrick Michl
    Dept of Internal Medicine IV, University Hospital Heidelberg, Heidelberg 69120, Germany
  • Markus W. Löffler
    Markus W. Löffler
    Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen 72076, Germany
    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, University of Tübingen, Tübingen 72076, Germany
    Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen 72076, Germany
    Department of Immunology, University of Tübingen, Tübingen 72076, Germany
    Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen 72076, Germany
  • Alfred Königsrainer*
    Alfred Königsrainer
    Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen 72076, Germany
    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, University of Tübingen, Tübingen 72076, Germany
    Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen 72076, Germany
    *[email protected]
  • , and 
  • Christoph Trautwein*
    Christoph Trautwein
    Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Tübingen 72076, Germany
    Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen 72076, Germany
    M3 Research Center for Malignome, Metabolome and Microbiome, Faculty of Medicine University Tübingen, Tübingen 72076, Germany
    *[email protected]
Cite this: J. Proteome Res. 2024, 23, 4, 1249–1262
Publication Date (Web):February 26, 2024
https://doi.org/10.1021/acs.jproteome.3c00611
Copyright © 2024 The Authors. Published by American Chemical Society

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    Abstract

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    Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose in the early stages and lacks reliable biomarkers. The scope of this project was to establish quantitative nuclear magnetic resonance (NMR) spectroscopy to comprehensively study blood serum alterations in PDAC patients. Serum samples from 34 PDAC patients obtained before and after pancreatectomy as well as 83 age- and sex-matched control samples from healthy donors were analyzed with in vitro diagnostics research (IVDr) proton NMR spectroscopy at 600 MHz. Uni- and multivariate statistics were applied to identify significant biofluid alterations. We identified 29 significantly changed metabolites and 98 lipoproteins when comparing serum from healthy controls with those of PDAC patients. The most prominent features were assigned to (i) markers of pancreatic function (e.g., glucose and blood triglycerides), (ii) markers related to surgery (e.g., ketone bodies and blood cholesterols), (iii) PDAC-associated markers (e.g., amino acids and creatine), and (iv) markers for systemic disturbances in PDAC (e.g., gut metabolites DMG, TMAO, DMSO2, and liver lipoproteins). Quantitative serum NMR spectroscopy is suited as a diagnostic tool to investigate PDAC. Remarkably, 2-hydroxybutyrate (2-HB) as a previously suggested marker for insulin resistance was found in extraordinarily high levels only after pancreatectomy, suggesting this metabolite is the strongest marker for pancreatic loss of function.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jproteome.3c00611.

    • Supplementary methods 1.1: Chemometrics, 1.2: Comparative statistics, and 1.3: Univariate and multivariate analysis; Table S1: Overview of downregulated parameters in pancreatic ductal adenocarcinoma patients’ samples after the surgery; Table S2: p-value and FDR of the significant parameters in preoperative and postoperative samples by volcano plot; Table S3: Mean and standard deviation of the parameters in preoperative (P1) and postoperative samples (P2); Table S4: Spearman’s correlation test result of 2-hydroxybutyrate in preoperative samples; Table S5: Spearman’s correlation test result of 3-hydroxybutyrate in preoperative samples; Table S6: Pearson’s correlation test result of 2-hydroxybutyrate in postoperative samples; Table S7: Pearson correlation test result of 3-hydroxybutyrate in postoperative samples; Table S8: p-value and FDR of significant parameters in preoperative and postoperative samples by comparative statistics; Table S9: p-value and FDR of significant metabolites between healthy controls, preoperative, and postoperative samples by comparative statistics; Table S10: p-value and FDR of significant lipoproteins between healthy controls, preoperative, and postoperative samples by comparative statistics; Table S11: Mean and standard deviation of the parameters relative to the extent of pancreatectomy; Table S12: p and FDR of the significant metabolites relative to the extent of pancreatectomy; Table S13: Variation importance in projection score of metabolites in the model between healthy, preoperative, and level of the extent of pancreatectomy; Table S14: Variation importance in projection score of lipoproteins in the model between healthy, preoperative, and level of the extent of pancreatectomy; Table S15: p and FDR value of the significant metabolites and lipoproteins between healthy, preoperative, and level of the extent of pancreatectomy; Table S16: Summary of patient characteristics; Table S17: Summary of healthy cohort characteristics; Table S18: Key NMR and laboratory parameters as potential markers associated with pancreatic function, surgery, PDAC, and systemic disturbances in PDAC; Figure S1: Altered NMR and clinical parameters of PDAC patients before and after surgery; Figure S2: Overview of altered parameters in pancreatic ductal adenocarcinoma patients’ samples before and after surgery; Figure S3: Results of each validation test, control group population, and comparative statistics of WBC between preoperative and postoperative samples; Figure S4: Metabolic differences according to the extent of pancreatectomy; Figure S5: Results of lipoproteomics based on level of the extent of pancreatectomy; Figure S6: Results of NMR-based inflammation analysis based on level of the extent of pancreatectomy; Figure S7: Results of PLS-DA permutation test and cross-validation of level of the extent of pancreatectomy based on metabolites and lipoproteins; Figure S8: Spectra of 2-HB and 3-HB recorded in 1D-NOESY and CPMG (PDF)

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