Elucidating the tumor microenvironment of IDH mutated gliomas

• Applicant: Dr. Sevin Turcan, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424180224

Recurrent mutations in IDH are found in ~80% of lower grade gliomas. IDH mutations produce the oncometabolite, 2-Hydroxyglutarate (2-HG), that accumulates to millimolar levels in the tumor. Majority of studies, including our previous work, has focused on tumor intrinsic effects of mutated IDH1 and revealed the role of 2-HG on proliferation, differentiation and epigenome alteration of glioma cells. However, the effect of extracellular 2-HG on the brain tumor microenvironment has not yet been well described. We hypothesize that 2-HG will help reshape the tumor microenvironment to create a permissive niche for tumor growth. Therefore, the overall goal of this proposal is to understand how extracellular 2-HG effects specific cell types (with a particular focus on microglia, macrophages and neurons). Towards this goal, we will integrate high-throughput microscopy (Osten lab) with functional glioma genomics (Turcan lab) to create a high-resolution map of the IDH mutated glioma tumor microenvironment. Our hope is that a greater understanding of how gliomas interact with the microenvironment will provide novel insights for the treatment of this disease. We plan to accomplish our objective by pursuing the following 3 specific aims:In Aim 1, we will describe the interaction of IDH mutant tumor cells with microglia and tumor-associated macrophages. Previous studies have shown that IDH mutations lead to immune suppression. However, our understanding of how 2-HG affects microglia and macrophages during gliomagenesis is still in its infancy. Our goal in this aim is to understand the distribution and infer the activation state of microglia and macrophages during early and late phases of IDH mutant glioma growth.In Aim 2, we will elucidate the interplay between IDH mutant tumor cells and neurons. We hypothesize that 2-HG generated by IDH mutation will impact neuronal activity during tumor initiation and growth. In this aim, we plan to use in vitro and in vivo models to understand the extent to which 2-HG modulates neuronal activity, and whether inhibition of 2-HG with small molecule inhibitors has an impact on altering neuronal activity.In Aim 3, we will determine the effect of mutant IDH1 on the transcriptional and chromatin states of brain tumor microenvironment. Our previous work has mainly focused on the molecular and epigenetic alterations in IDH mutated tumors and cell line models. In this aim, we will use next-generation sequencing to decipher the transcriptional and epigenetic states of non-malignant cells that are either exposed to 2-HG in vitro or in vivo.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Dr. Pavel Osten