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Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression.

Glioblastoma (GBM) therapy could strongly profit from simplified procedures for personalized medicine. Cannabidiol (CBD) is explored for GBM-patients, but the mode of drug-action is largely unknown and stratification markers are missing. We investigated CBD-induced cytotoxicity in a panel of human primary GBM cells as well as transgenic mouse gliomas and in different orthotopic or transgenic in vivo models. We observed therapeutic efficiency of CBD in a subset of GBM, obtained genetic markers indicating CBD-sensitive GBM and found that the p53 status segregated cell-death modes. Genome wide loss of function screening, transcription factor binding studies and knockout-models indicated a central for role for NFkB (RelA) in CBD-initiated GBM-death. CBD mediated nuclear import of RelA lacking an essential post-translational modification and reduced RelA-activity. CBD altered redox levels specifically in drug-sensitive GBM and ROS-levels in unstimulated GBM predicted therapeutic response. Hence, quantifying ROS in GBM represents a simple bioassay to identify individuals potentially profiting from CBD-application in neurooncology.

OBJECTIVE: Data from mouse models suggest that high-grade gliomas (HG-gliomas) origin from somatic mutant neural stem and precursor cells (NPCs). We found that endogenous NPCs also defend the brain against HG-gliomas. Here, we describe the signal transduction mechanism of NPC-mediated tumor suppression and present data on the tropism of endogenous NPCs to human HG-gliomas. METHODS: For our experiments, we used transgenic mouse models, human HG-glioma biopsies, molecular biology techniques (microarrays, real-time PCR, mass-spectrometry, array-CGH, fluorescence in situ hybridization), cell-culture (primary NPC- and glioma cultures of human and murine origin), immunohistochemistry and survival studies in orthotopic mouse tumour models. RESULTS: NPCs migrate from the subventricular zone to HG-gliomas, reduce glioma expansion and prolong survival by releasing a group of fatty acid ethanolamides that have agonistic activity on the vanilloid receptor (transient receptor potential vanilloid subfamily member-1; TRPV1). TRPV1 expression is much higher in HG-gliomas than in tumor-free brain and TRPV1 stimulation triggers tumor cell death. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloids suggesting that TRPV1 agonists hold potential as new HGastrocytoma therapeutics. Furthermore, we analyzed the tumor-parenchyma interface of neurosurgical resections for the presence of NPCs and distinguished these physiological cells from the tumor mass. We observed that PSA-NCAM-positive NPCs, which are genetically distinct from the the tumor mass, accumulate at the border of high-grade gliomas and display a marker profile consistent with immature migratory neuronal progenitor cells. CONCLUSION: Overall, our data reveal a mechanism for NPC attraction CNS tumors and suggest that NPCs accumulate in human high-grade astrocytomas. In mouse models NPCs suppress HG-gliomas and the endogenous anti-tumorigenic factors can be used as pre-clinical HG-glioma therapeutics.

Objective: Glioblastomas are the most aggressive primary brain tumors in humans. Microglia/brain macrophage accumulation in and around the tumor correlates with malignancy and poor clinical prognosis of these tumors. We have previously shown that microglia promote glioma expansion through upregulation[for full text, please go to the a.m. URL], 65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)