Cnsc-04. Decoding the Spatial Architecture of Integrated Electrophysiological and Transcriptomic Diversity in Malignant Brain Tumors
Year: 2025
Type: conference-abstract
Abstract: Glioma cells form synaptic connections with neurons, facilitating tumor progression and therapeutic resistance, yet the microenvironmental drivers of this synaptogenesis remain unclear. To investigate the mechanisms regulating neuron-glioma connectivity, we developed ElectroGenomics, an integrative spatial electrophysiology and transcriptomics approach combining high-density multielectrode array (HD-MEA) recordings, spatial transcriptomics, retrograde tracing, and graph-based network analysis. Applying this framework across human cortical slice cultures and murine glioma models, we found that tumor infiltration induces localized peritumoral hyperexcitability alongside inflammatory activation of microglia. In particular, SPP1+/TREM2+ microglia, resembling damage-associated states observed in stroke and trauma, were found to drive BDNF-mediated synaptogenesis and facilitate neuron-tumor network formation through close spatial interactions with NPC/OPC-like tumor cells and sprouting neurons. Using optogenetic stimulation of cortical neurons in a patient-derived xenograft model, we confirmed that increased neuronal activity promotes the recruitment and activation of SPP1+ microglia specifically within the tumor-infiltrative regions. Pathway analysis further identified STAT3 signaling as a central driver of this glioma-associated microglial phenotype. Pharmacological inhibition of STAT3 signaling or depletion of microglia significantly disrupted neuron-glioma connectivity and reduced neural circuit integration in human neocortical slice models. Complementary functional calcium imaging demonstrated that STAT3 inhibition led to decreased intratumoral signaling and diminished neuron-glioma synapse formation. Together, our study identifies glioma-associated SPP1+/TREM2+ microglia as key regulators of neuron-glioma synapse formation and highlights the STAT3 pathway as a promising therapeutic target to disrupt glioma integration into brain circuitry.
Source: Neuro-Oncology
Authors: Elena Grabis, Louis Hilfiger, Giulia Villa, Jean-Philipp Waldmann, Richard Drexler, Rebecca Mancusi, Junyi Zhang, Yahaya A Yabo, Lynn Menzl, Jan Kueckelhaus, Tao Peng, Levi van Hijfte, Marco Mühlbauer, Georg Kastner, Youran Kong, Philipp Heinrichs, Ata Merdan, Abdelhamid Sta, Jakob Strähle, Nicolas Neidert, Jasim Kada Benotmane, Ekin Reyhan, Svenja K Tetzlaff, Dolores Hambardzumyan, Sebastian Lillo, Thomas Daubon, Adam M Sonabend, Catalina Lee Chang, Atique Ahmed, Anna Golebiewska, Florian Putz, Ingmar Bluemcke, Lucas Hoffmann, Roman Sankowski, Michelle Monje, Oliver Schnell, Juergen Beck, Marco Prinz, Andreas Vlachos, Franz Ricklefs, Varun Venkataramani, Dieter Henrik Heiland
Institutions: University of Freiburg, University Medical Center Freiburg, Friedrich-Alexander-Universität Erlangen-Nürnberg, Stanford Medicine, Stanford University, Heidelberg University, University Hospital Heidelberg, National Center for Tumor Diseases, Icahn School of Medicine at Mount Sinai, Centre National de la Recherche Scientifique, Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, Northwestern University, Northwestern Medicine, Luxembourg Institute of Health, Universitätsklinikum Erlangen, University Medical Center Hamburg-Eppendorf
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416140903
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