Metabolic Profiling of Thymic Epithelial Tumors Hints to a Strong Warburg Effect, Glutaminolysis and Precarious Redox Homeostasis as Potential Therapeutic Targets

Mohammad Alwahsh, Robert Knitsch, Rosemarie Marchan, Jörg Lambert, Christian Hoerner, Xiaonan Zhang, Berthold Schalke, De Hyung Lee, Elena Bulut, Thomas Graeter, German Ott, Katrin S. Kurz, Gerhard Preissler, Sebastian Schölch, Joviana Farhat, Zhihan Yao, Carsten Sticht, Philipp Ströbel, Roland Hergenröder, Alexander MarxDjeda Belharazem

    Research output: Contribution to journalArticlepeer-review

    6 Scopus citations

    Abstract

    Thymomas and thymic carcinomas (TC) are malignant thymic epithelial tumors (TETs) with poor outcome, if non-resectable. Metabolic signatures of TETs have not yet been studied and may offer new therapeutic options. Metabolic profiles of snap-frozen thymomas (WHO types A, AB, B1, B2, B3, n = 12) and TCs (n = 3) were determined by high resolution magic angle spinning 1H nuclear magnetic resonance (HRMAS 1H-NMR) spectroscopy. Metabolite-based prediction of active KEGG metabolic pathways was achieved with MetPA. In relation to metabolite-based metabolic pathways, gene expression signatures of TETs (n = 115) were investigated in the public “The Cancer Genome Atlas” (TCGA) dataset using gene set enrichment analysis. Overall, thirty-seven metabolites were quantified in TETs, including acetylcholine that was not previously detected in other nonendocrine cancers. Metabolite-based cluster analysis distinguished clinically indolent (A, AB, B1) and aggressive TETs (B2, B3, TCs). Using MetPA, six KEGG metabolic pathways were predicted to be activated, including proline/arginine, glycolysis and glutathione pathways. The activated pathways as predicted by metabolite-profiling were generally enriched transcriptionally in the independent TCGA dataset. Shared high lactic acid and glutamine levels, together with associated gene expression signatures suggested a strong “Warburg effect”, glutaminolysis and redox homeostasis as potential vulnerabilities that need validation in a large, independent cohort of aggressive TETs. If confirmed, targeting metabolic pathways may eventually prove as adjunct therapeutic options in TETs, since the metabolic features identified here are known to confer resistance to cisplatin-based chemotherapy, kinase inhibitors and immune checkpoint blockers, i.e., currently used therapies for non-resectable TETs.

    Original languageBritish English
    Article number1564
    JournalCancers
    Volume14
    Issue number6
    DOIs
    StatePublished - 1 Mar 2022

    Keywords

    • Biomarker
    • HRMAS H-NMR
    • Metabolomics
    • Thymic carcinoma
    • Thymoma

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