Functional noninvasive detection of glycolytic pancreatic ductal adenocarcinoma.

Autor:	Heid I; Institute of Diagnostic and Interventional Radiology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Münch C; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany., Karakaya S; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany., Lueong SS; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany., Winkelkotte AM; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Liffers ST; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany., Godfrey L; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany., Cheung PFY; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany., Savvatakis K; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany., Topping GJ; Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Englert F; Institute of Diagnostic and Interventional Radiology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Kritzner L; Institute of Diagnostic and Interventional Radiology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Grashei M; Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Tannapfel A; Institute of Pathology, Ruhr University of Bochum, Bochum, Germany., Viebahn R; Department of Surgery, Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, Germany., Wolters H; Department of Visceral and General Surgery, St. Josef-Hospital, Dortmund, Germany., Uhl W; Clinic for General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany., Vangala D; Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany., Smeets EMM; Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands., Aarntzen EHJG; Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands., Rauh D; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) Am Zentrum Für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany., Weichert W; Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.; Comprehensive Cancer Center Munich (CCCM), Munich, Germany., Hoheisel JD; Division of Functional Genome Analysis, German Cancer Research Center, DKFZ, Heidelberg, Germany., Hahn SA; Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, 44780, Bochum, Germany., Schilling F; Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany., Braren R; Institute of Diagnostic and Interventional Radiology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany., Trajkovic-Arsic M; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. m.trajkovic-arsic@dkfz.de.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. m.trajkovic-arsic@dkfz.de.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany. m.trajkovic-arsic@dkfz.de., Siveke JT; West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. j.siveke@dkfz.de.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. j.siveke@dkfz.de.; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany. j.siveke@dkfz.de.
Jazyk:	angličtina
Zdroj:	Cancer & metabolism [Cancer Metab] 2022 Dec 09; Vol. 10 (1), pp. 24. Date of Electronic Publication: 2022 Dec 09.
DOI:	10.1186/s40170-022-00298-5
Abstrakt:	Background: Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatment options beyond chemotherapy. Although molecular subtypes such as classical and QM (quasi-mesenchymal)/basal-like with transcriptome-based distinct signatures have been identified, deduced therapeutic strategies and targets remain elusive. Gene expression data show enrichment of glycolytic genes in the more aggressive and therapy-resistant QM subtype. However, whether the glycolytic transcripts are translated into functional glycolysis that could further be explored for metabolic targeting in QM subtype is still not known. Methods: We used different patient-derived PDAC model systems (conventional and primary patient-derived cells, patient-derived xenografts (PDX), and patient samples) and performed transcriptional and functional metabolic analysis. These included RNAseq and Illumina HT12 bead array, in vitro Seahorse metabolic flux assays and metabolic drug targeting, and in vivo hyperpolarized [1- 13 C]pyruvate and [1- 13 C]lactate magnetic resonance spectroscopy (HP-MRS) in PDAC xenografts. Results: We found that glycolytic metabolic dependencies are not unambiguously functionally exposed in all QM PDACs. Metabolic analysis demonstrated functional metabolic heterogeneity in patient-derived primary cells and less so in conventional cell lines independent of molecular subtype. Importantly, we observed that the glycolytic product lactate is actively imported into the PDAC cells and used in mitochondrial oxidation in both classical and QM PDAC cells, although more actively in the QM cell lines. By using HP-MRS, we were able to noninvasively identify highly glycolytic PDAC xenografts by detecting the last glycolytic enzymatic step and prominent intra-tumoral [1- 13 C]pyruvate and [1- 13 C]lactate interconversion in vivo. Conclusion: Our study adds functional metabolic phenotyping to transcriptome-based analysis and proposes a functional approach to identify highly glycolytic PDACs as candidates for antimetabolic therapeutic avenues. (© 2022. The Author(s).)
Databáze:	MEDLINE
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