Oncometabolite D-2-HydroxyGlutarate causes reactive astrogliosis in IDH mutant glioma microenvironment.

• Applicant: Vidhya Madapusi Ravi, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521419277

IDH1/2 mutated glioma are a distinct group of brain tumors that differ from IDH-wildtype glioma in several aspects besides clinical prognosis. A crucial factor for the growth and invasive behavior of glioma is the tumor microenvironment and its supportive or inhibitory impact on the tumor. We have demonstrated that both astrocytes and microglia engage in non-inflammatory transformation in IDH wild-type gliomas which promote an immunosuppressive milieu. Consequently, anti-tumor immunity is suppressed and concurrently prooncogenic stimuli from myeloid cells and astrocytes promote tumor growth. Some of these prooncogenic effects have been shown to be mediated by the oncometabolite R-2HG in IDH-mutated tumors. Most recently, the impact of R-2HG on T cells was investigated, confirming that the R-2HG has a major impact on various cells of the IDH mutated tumor microenvironment. The extent to which other cell types such as astrocytes, microglia and neurons are altered by D-2-HG remains poorly explored. In this project, we aim to explore the transcriptional diversity of astrocytes in IDH mutated gliomas and the underlying mechanism that drive the reactive transformation. Through in-depth profiling of tumor-associated astrocytes, we will curate a resource dataset as reference for further research. Based on this profiling, we will subsequently explore the electrophysiological aspect of the environment using our established neocortical slice model. In Brief: In this study , we want to study the impact of the “oncometabolite D-2HG and reactive astrogliosis in IDH-mutant glioma environment” using transcriptomics and electrophysiology experiments.

• DFG Programme: Research Grants