DKFZ Junior Group Brain Cancer Metabolism

Dr. Christiane Opitz

Evidence emerging in the last years has led to the re-appreciation of the central role of altered cell metabolism in cancer. We have identified a metabolic pathway of the essential amino acid tryptophan as a key element promoting malignant brain tumors. Tryptophan metabolites activate the dioxin receptor resulting in enhanced invasiveness and clonogenicity of brain tumor cells and increased formation of brain tumors. While the role of the dioxin receptor in cancer biology is well established, the signaling pathways through which the dioxin receptor promotes cancer are poorly understood. Due to the fact that tryptophan metabolites as (patho-)physiologically relevant endogenous dioxin receptor ligands were just identified, the signaling pathways activated by these endogenous dioxin receptor ligands remain elusive. As different dioxin receptor ligands exert diverse biological effects, it is expected that tryptophan metabolites will activate other signaling pathways than the classical and well-studied exogenous ligand dioxin. Inhibition of the dioxin receptor may be a new approach for cancer therapy. Understanding the downstream signaling pathways that are responsible for the tumor-promoting effects of endogenous dioxin receptor activation may identify more specific therapeutic targets for the treatment of tumors that rely on this pathway and and reveal potential biomarkers for monitoring biological activity of these pathways.

In the future we plan to identify the signaling pathways activated by tryptophan degradation in brain tumor cells. Specifically we will analyze the signaling pathways downstream of endogenous dioxin receptor signaling and the signaling pathways activated by tryptophan depletion. In addition we aim to use our expertise in monitoring cancer metabolism for the analysis of nicotinamide metabolism in brain tumors. Preliminary evidence suggests that several enzymes implicated in nicotinamide metabolism are overexpressed in brain tumors. Our group aims at delineating the role of nicotinamide metabolism in brain tumors by targeted metabolomics and bioinformatics approaches using malignant brain tumor cells and tumor stem cells. If the metabolism of nicotinamide is found to be functionally relevant for the malignant phenotype or the treatment resistance of brain tumors, small molecule screens will be performed to identify inhibitors of the respective enzymes. In addition, nicotinamide will be measured in biofluids of brain tumor patients and correlated with the activity of the respective enzymes in the tumor tissue with the aim of identifying biomarkers for the activity of nicotinamide metabolism for future stratification of patients to treatment with inhibitors of this pathway. In addition, “metabolic flux analyses” will be used to model tryptophan and nicotinamide metabolism.

Contact

Dr. Christiane Opitz
Brain Cancer Metabolism (B350)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 423839

Selected Publications

  • Sadik A*, Somarribas Patterson LF*, Öztürk S*, Mohapatra SR*, Panitz V, Secker PF, Pfänder P, Loth S, Salem H, Prentzell MT, Berdel B, Iskar M, Faessler E, Reuter F, Kirst I, Kalter V, Foerster KI, Jäger E, Guevara CR, Sobeh M, Hielscher T, Poschet G, Reinhardt A, Hassel JC, Zapatka M, Hahn U, von Deimling A, Hopf C, Schlichting R, Escher BI, Burhenne J, Haefeli WE, Ishaque N, Böhme A, Schäuble S, Thedieck K, Trump S*, Seiffert M*, Opitz CA*#. IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell. 2020 Aug 17:S0092-8674(20)30946-6.
  • Mohapatra SR, Sadik A, Tykocinski LO, Dietze J, Poschet G, Heiland I, Opitz CA. Hypoxia Inducible Factor 1? Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma. Front Immunol. 2019 Dec 4;10:2762. doi: 10.3389/fimmu.2019.02762. eCollection 2019. PubMed PMID: 31866995
  • Adam I, Dewi DL, Mooiweer J, Sadik A, Mohapatra SR, Berdel B, Keil M, Sonner JK, Thedieck K, Rose AJ, Platten M, Heiland I, Trump S, Opitz CA. Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation. Oncoimmunology. 2018 Sep 5;7(12):e1486353. doi:10.1080/2162402X.2018.1486353. eCollection 2018. PubMed PMID: 30524887
  • Dewi, D.L., Mohapatra, S.R., Cabañes, S.B., Adam, I., Patterson, L.F.S., Berdel, B., Kahloon, M., Thürmann, L., Loth, S., Heilmann, K., Weichenhan, D., Mücke, O., Heiland, I., Wimberger, P., Kuhlmann, J.D., Kellner, K.-H., Schott, S., Plass, C., Platten, M., Gerhäuser, C., Trump, S., Opitz, C.A., (2017): Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer. Oncoimmunology. 2017;6(2):e1274477. doi: 10.1080/2162402X.2016.1274477.
to top
powered by webEdition CMS