Spatially Restricted Immature Neuronal Programs Drive Functional Connectivity in Glioblastoma

Delev D, Yang D, Grabis E, Ort J, Bak A, Bárány L, Villa G, Waldmann JP, Van Loo KMJ, Schünemann KD, Peter S, Wu Y, Hamou H, Menzl L, Vladimirov T, Frank K, Peng T, van Hijfte L, Mühlbauer M, Kastner G, Ricklefs F, Merdan A, Dörfler A, Müller-Voggel N, Blümcke I, Hoffmann L, Venkataramani V, Beckervordersandforth R, Sankowski R, Prinz M, Beck J, Weber YG, Schnell O, Clusmann H, Rampp S, Feldmeyer D, Koch H, Heiland DH (2026)

Publication Status: In review

Publication Type: Unpublished / Preprint

Future Publication Type: Journal article

Publication year: 2026

DOI: 10.2139/ssrn.6352483

Abstract

Glioblastoma (GB) integrates into the human brain by exploiting spatially restricted neuronal microenvironments at tumor margins. Combining magnetoencephalography-based functional mapping in patients with GB, spatially resolved biopsies, single-cell RNA sequencing, spatial transcriptomics, and electrophysiological profiling in human cortical slice models, we identify peritumoral connectivity hubs enriched for synaptogenic and immature neuronal programs. Connectivity-rich regions preferentially involve projection-capable excitatory neurons and display convergent activation of the WNK-SPAK-NKCC1 chloride homeostasis, consistent with a reduction in inhibition via GABAergic transmission in peritumoral neurons. GB-conditioned neurons exhibit developmental regression, impaired inhibitory control, and immature dendritic spine remodeling while network-level recordings reveal a GABA-sensitive reorganization of circuit topology. NKCC1 blockade reduces tumor-neuron synaptic integration and dampens functional network connectivity. Clinically, peritumoral degree centrality is an independent predictor of survival beyond established covariates. These findings establish neuronal immaturity as a functional substrate for tumor-neuron connectivity and define actionable biomarkers and pathways at the tumor-brain interface. 

Authors with CRIS profile

Daniel Delev Department of Neurosurgery László Bárány Department of Neurosurgery Jean-Philipp Waldmann Department of Neurosurgery Lynn Menzl Department of Neurosurgery Tim Vladimirov Department of Neurosurgery Katharina Frank Department of Neurosurgery Tao Peng Department of Neurosurgery Levi van Hijfte Department of Neurosurgery Arnd Dörfler Lehrstuhl für Neuroradiologie Nadia Müller-Voggel Department of Neurosurgery Ingmar Blümcke Lehrstuhl für Neuropathologie Lucas Hoffmann Institute of Neuropathology Ruth Beckervordersandforth-Bonk Professur für Molekulare Neuropathologie (Heisenberg-Professur) Oliver Schnell Lehrstuhl für Neurochirurgie Stefan Rampp Department of Neurosurgery Dieter Henrik Heiland Department of Neurosurgery

Additional Organisation(s)

Sonderforschungsbereich 1540/1 - Erforschung der Mechanik des Gehirns (EBM): Verständnis, Engineering und Nutzung mechanischer Eigenschaften und Signale in der Entwicklung, Physiologie und Pathologie des zentralen Nervensystems

Involved external institutions

Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Universitätsklinikum Aachen (UKA) DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Forschungszentrum Jülich / Research Centre Jülich (FZJ) DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Universitätsklinikum Freiburg DE Germany (DE)

How to cite

APA:

Delev, D., Yang, D., Grabis, E., Ort, J., Bak, A., Bárány, L.,... Heiland, D.H. (2026). Spatially Restricted Immature Neuronal Programs Drive Functional Connectivity in Glioblastoma. (Unpublished, In review).

MLA:

Delev, Daniel, et al. Spatially Restricted Immature Neuronal Programs Drive Functional Connectivity in Glioblastoma. Unpublished, In review. 2026.

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