Theranostics 2021; 11(19):9217-9233. doi:10.7150/thno.60679

Research Paper

Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma

Verena Panitz1,2*, Saša Končarević3*, Ahmed Sadik1,4*, Dennis Friedel1,4, Tobias Bausbacher5, Saskia Trump6, Vadim Farztdinov3#, Sandra Schulz5, Philipp Sievers7,8, Stefan Schmidt5, Ina Jürgenson1,2, Stephan Jung3, Karsten Kuhn3, Irada Pflüger9, Suraj Sharma10, Antje Wick2, Pauline Pfänder1,4, Stefan Selzer3, Philipp Vollmuth9, Felix Sahm7,8, Andreas von Deimling7,8, Ines Heiland10, Carsten Hopf5, Peter Schulz-Knappe, Ian Pike11, Michael Platten12,13, Wolfgang Wick2,14, Christiane A. Opitz1,2✉

1. DKTK Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2. Department of Neurology and National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany.
3. Proteome Sciences R&D GmbH & Co. KG, Altenhöferallee 3, 60438 Frankfurt/Main, Germany.
4. Faculty of Bioscience, Heidelberg University, 69120 Heidelberg, Germany.
5. Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences, 68163 Mannheim, Germany.
6. Molecular Epidemiology Unit, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
7. Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
8. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
9. Department of Neuroradiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
10. Department of Arctic and Marine Biology, UiT, The Arctic University of Norway, 9037 Tromsø, Norway.
11. Proteome Sciences plc, 5 Dashwood Lang Road, Bourne Business Park, Addlestone, Surrey KT15 2HJ, United Kingdom.
12. Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
13. DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
14. Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
*These authors contributed equally to this work.
#Current address: Core Facility - High-Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), 10117 Berlin, Germany.
§Current address: Mittelorbroich 125, 47839 Krefeld, Germany.

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Citation:
Panitz V, Končarević S, Sadik A, Friedel D, Bausbacher T, Trump S, Farztdinov V, Schulz S, Sievers P, Schmidt S, Jürgenson I, Jung S, Kuhn K, Pflüger I, Sharma S, Wick A, Pfänder P, Selzer S, Vollmuth P, Sahm F, von Deimling A, Heiland I, Hopf C, Schulz-Knappe P, Pike I, Platten M, Wick W, Opitz CA. Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma. Theranostics 2021; 11(19):9217-9233. doi:10.7150/thno.60679. Available from https://www.thno.org/v11p9217.htm

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Abstract

Tryptophan (Trp)-catabolic enzymes (TCEs) produce metabolites that activate the aryl hydrocarbon receptor (AHR) and promote tumor progression and immunosuppression in glioblastoma. As therapies targeting TCEs or AHR become available, a better understanding of Trp metabolism is required.

Methods: The combination of LC-MS/MS with chemical isobaric labeling enabled the simultaneous quantitative comparison of Trp and its amino group-bearing metabolites in multiple samples. We applied this method to the sera of a cohort of 43 recurrent glioblastoma patients and 43 age- and sex-matched healthy controls. Tumor volumes were measured in MRI data using an artificial neural network-based approach. MALDI MSI visualized Trp and its direct metabolite N-formylkynurenine (FK) in glioblastoma tissue. Analysis of scRNA-seq data was used to detect the presence of Trp metabolism and AHR activity in different cell types in glioblastoma.

Results: Compared to healthy controls, glioblastoma patients showed decreased serum Trp levels. Surprisingly, the levels of Trp metabolites were also reduced. The decrease became smaller with more enzymatic steps between Trp and its metabolites, suggesting that Trp availability controls the levels of its systemic metabolites. High tumor volume associated with low systemic metabolite levels and low systemic kynurenine levels associated with worse overall survival. MALDI MSI demonstrated heterogeneity of Trp catabolism across glioblastoma tissues. Analysis of scRNA-seq data revealed that genes involved in Trp metabolism were expressed in almost all the cell types in glioblastoma and that most cell types, in particular macrophages and T cells, exhibited AHR activation. Moreover, high AHR activity associated with reduced overall survival in the glioblastoma TCGA dataset.

Conclusion: The novel techniques we developed could support the identification of patients that may benefit from therapies targeting TCEs or AHR activation.

Keywords: Glioblastoma, tryptophan, AHR, mass spectrometry, MALDI MSI