TY - JOUR
T1 - Metabolic Profiling of Thymic Epithelial Tumors Hints to a Strong Warburg Effect, Glutaminolysis and Precarious Redox Homeostasis as Potential Therapeutic Targets
AU - Alwahsh, Mohammad
AU - Knitsch, Robert
AU - Marchan, Rosemarie
AU - Lambert, Jörg
AU - Hoerner, Christian
AU - Zhang, Xiaonan
AU - Schalke, Berthold
AU - Lee, De Hyung
AU - Bulut, Elena
AU - Graeter, Thomas
AU - Ott, German
AU - Kurz, Katrin S.
AU - Preissler, Gerhard
AU - Schölch, Sebastian
AU - Farhat, Joviana
AU - Yao, Zhihan
AU - Sticht, Carsten
AU - Ströbel, Philipp
AU - Hergenröder, Roland
AU - Marx, Alexander
AU - Belharazem, Djeda
N1 - Funding Information:
Acknowledgments: Support from the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, dem Regierenden Bürgermeister von Berlin, Senatskanzlei Wissenschaft und Forschung and the Bundesministerium für Bildung und Forschung (01KU1216I) is gratefully acknowledged. And the publication of this article was funded by the Open Access Fund of the Leibniz Association.
Funding Information:
Funding: This work was supported by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, and the Bundesministerium für Bildung und Forschung (01KU1216I). Sebastian Schölch is generously funded by Hector Stiftung II.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - Biomarker
KW - HRMAS H-NMR
KW - Metabolomics
KW - Thymic carcinoma
KW - Thymoma
UR - http://www.scopus.com/inward/record.url?scp=85126522441&partnerID=8YFLogxK
U2 - 10.3390/cancers14061564
DO - 10.3390/cancers14061564
M3 - Article
AN - SCOPUS:85126522441
SN - 2072-6694
VL - 14
JO - Cancers
JF - Cancers
IS - 6
M1 - 1564
ER -