Division of Metabolic crosstalk in cancer

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.