Bdnf-Trkb Signaling Regulates Neuron-Glioma Synaptogenesis And Promotes Tumor Progression

Abstract Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs hijack mechanisms of brain development and plasticity to their advantage. Here, we investigated the role of microenvironmental BDNF on pediatric gliomas, independent of the NTRK fusion events commonly identified in infant HGG. Genetic deletion or pharmacological blockade of NTRK2 (TrkB), in patient-derived pediatric glioma increases survival in multiple DIPG and pGBM patient-derived orthotopic xenograft models. Unlike the paracrine BDNF-TrkB signaling observed between subpopulations of adult HGG malignant cells, pediatric glioma express TrkB, but not BDNF ligand. BDNF is secreted by normal brain cells in response to neuronal activity and conditioned medium experiments from cortical slices of mice indicates the brain microenvironment as the chief source of BDNF ligand. Addition of recombinant BDNF protein increases pediatric glioma cell proliferation and activates the canonical downstream MAPK signaling pathway, an effect that is blocked by genetic or pharmacological TrkB inhibition in pHGG. However, the glioma growth-promoting effects of BDNF in vivo cannot be explained by stimulation of MAPK signaling alone. We therefore examined the effects of BDNF signaling on neuron-to-glioma synapse formation, a newly recognized microenvironmental interaction important for pediatric glioma progression. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis in neuron-glioma co-culture. We are presently exploring the role for BDNF-TrkB signaling in glioma synaptic plasticity and function. Funding: Abbie’s Army Foundation