Investigating the interaction of high-grade gliomas and microglial cells

• Antragsteller: Professor Dr. Helmut Kettenmann; Professor Dr. Michael Synowitz
• Fachliche Zuordnung: Klinische Neurologie; Neurochirurgie und Neuroradiologie
• Förderung: Förderung von 2013 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 237843485

Primary brain tumors, such as anaplastic astrocytoma and glioblastoma - hereafter referred to as high-grade glioma (HG-glioma) - belong to the most aggressive neoplasms in humans. HG-glioma are heterogeneous not only in their expression profile, but also in their cellular composition. A large fraction of the cells within a glioma are brain macrophages/microglial cells which can amount up to 30%. The goal of this proposal is to study interactions between HG-glioma and microglial cells and determine to which extend and by which mechanism microglia influence glioma growth and invasion in mouse models and in human. We, therefore, will establish a procedure to purify and culture human and mouse glioma-associated and non-associated microglial cells. Corresponding control (non-glioma-associated microglial cells) human cells will be obtained from patients with epileptic seizures that underwent temporal lobe surgery. In the mouse model we will also distinguish between blood-derived monocytes and microglia invaded from the brain parenchyma. Genetic profiling of the different microglial populations will indicate new pathways of microglia glioma interaction. One specific pathway that we have already identified is mediated by the metalloprotease MT1-MMP and we will further explore how glioma cells induce this microglial pro-tumorigenic factor. We will determine whether human glioma attracts microglia or whether human microglia promote glioma invasion and growth. We will also determine how bulk glioma cells and glioma stem cells differentially affect the microglial phenotype. We will characterize microglial-glioma interactions in human glioma tissue and in mouse models in vivo using 2-photon imaging. We will try to identify potential therapeutic targets that interfere with pathways of microglia glioma interactions with the ultimate goal to convert microglia from a pro- to an anti-tumorigenic phenotype.

• DFG-Verfahren: Sachbeihilfen