| Autor: |
Vidhya Ravi, Simon Behringer, Kevin Joseph, Luciana Haniball, Jan Kueckelhaus, Paulina Will, Nicolas Neidert, Jonathan Goeldner, Pamela Franco, Christian Fung, Juergen Beck, Roman Sankowski, Marco Prinz, Ulrich Hofmann, Oliver Schnell, Dieter Henrik Heiland |
| Rok vydání: |
2021 |
| Popis: |
Reactive transformation of astrocytes in IDH wild-type glioma contribute to anti-tumor immunity and support pro-oncogenic signaling. The role of intra- and peritumoral astrocytes in IDH1/2 mutated glioma, a prognostically beneficial subgroup with oncogene-driven enrichment of R-2-hydroxygluterate (2-HG) remains sparsely explored. 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. IDH-mutated glioma inoculation into human neocortical sections or treatment with R-2-HG resulted in an oncometabolite-mediated transcriptional shift towards inflammation in astrocytes. This transcriptional shift was found to be mediated by myeloid cell polarization through R-2-HG in the tumor microenvironment, which was further confirmed by selective depletion of myeloid cells. Integrative analysis of bulk RNA-sequencing of purified microglia, single-cell transcriptomics and spatially resolved transcriptomics confirmed this microglia-mediated inflammatory activation of astrocytes. This inflammatory activation is accompanied by loss of neurotransmitter homeostasis. Further, treatment of cortical sections with RH2G results in increased neuronal activity and LFP activity, pointing to the excitotoxic nature of RH2G in the neural microenvironment, with a significant loss of neurons with chronic treatment. The presented findings provide insights into the role that R-2HG plays in the reactive transformation of astrocytes within the IDH-mutated tumor environment and is fundamentally different that seen in IDH wildtype glioma. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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