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73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

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The role of onco-metabolite (R-2-hydroxyglutarate) in the IDH mutant glioblastoma microenvironment

Die Rolle des Onko-Metaboliten (R-2-Hydroxyglutarat) in der Mikroumgebung des IDH-mutierten Glioblastoms

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  • presenting/speaker Vidhya Madapusi Ravi - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Neuroelectronic Systems, Freiburg i. Br., Deutschland
  • Simon Behringer - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Neuroelectronic Systems, Freiburg i. Br., Deutschland
  • Kevin Joseph - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Jürgen Beck - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Oliver Schnell - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Dieter Henrik Heiland - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocP149

doi: 10.3205/22dgnc462, urn:nbn:de:0183-22dgnc4622

Published: May 25, 2022

© 2022 Ravi et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Objective: Recently, we found that the reactive astrocytes in the IDH wild type glioblastoma contribute to anti-tumor immunity and support pro-oncogenic signaling. Here, we characterized the transcriptomic signature of IDH1/2-mutant glioma associated astrocytes and determined a unique inflammatory transformation, profoundly different to astrocytes in IDH wildtype glioma patients due to an onco-metabolite R-2-hydroxyglutarate using Next generation sequencing and human ex-vivo slice model.

Methods: We purified and transcriptionally profiled astrocytes from 9 patients with confirmed IDH1-R132H mutation, by means of RNA-sequencing and the data were analyzed using the established pipelines. We also used spatial transcriptomics to evidently show the spatial distribution of astrocytes in IDH-mutated/wildtype glioma samples. We validated our findings using human organotypic slice model inoculated with IDH-mutant cell line or treated with oncometabolite 2-hydroxy glutarate. Additionally, LC-MS was further used to give us a chart of neurotransmitters due to altered microenvironment.

Results: Our results from RNA sequencing showed a transcriptional transformation of reactive astrocytes within the microenvironment of IDH-mutated tumors compared to wildtype glioma by means of RNA-sequencing of purified astrocytes. And, using our established human neocortical GBM model inoculated with IDH mutant tumor and R-2HG treatment, we showed that we were able to activate inflammatory transcriptional programs in astrocytes, mediated by the presence of microglia. Further, by spatially mapping the transcriptomic profiles of purified microglia, we were able to confirm that microglia also demonstrate inflammatory activation in IDH mutated glioma. This inflammatory astrocyte transformation is associated with a loss of neurotransmitter homeostasis (disrupted levels of glutamate) in the treated sections, as has been previously reported in IDH mutated tumors. Additionally, R-H2G increased neuronal spiking rate in, pointing to potential excitotoxicity.

Conclusion: Our results may provide a crucial contribution towards understanding the role of R-2HG in the IDH mutant glioma microenvironment and sheds light on the significant microenvironmental differences to IDH wild-type glioma.