gms | German Medical Science

72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

06.06. - 09.06.2021

Meclofenamate demolishes the network architecture and electrophysiological coupling of malignant gliomas

Meclofenamat führt zu einer funktionellen und morphologischen Zerstörung der interzellulären Netzwerkarchitektur des Glioblastoms

Meeting Abstract

  • presenting/speaker Matthias Schneider - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland; Universitätsklinikum Bonn, Department of Neuropathology, Bonn, Deutschland
  • Anna-Laura Potthoff - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland
  • Lea Vollmer - Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland
  • Vidhya Madapusi Ravi - Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland
  • Bernd O. Evert - Universitätsklinikum Bonn, Klinik für Neurologie, Bonn, Deutschland
  • Erdem Güresir - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland
  • Patrick Schuss - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland
  • Andreas Dolf - Universitätsklinikum Bonn, Institute of Experimental Immunology, Bonn, Deutschland
  • Mike-Andrew Westhoff - University Medical Center Ulm, Department of Pediatrics and Adolescent Medicine, Ulm, Deutschland
  • Jürgen Beck - Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland
  • Hartmut Vatter - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland
  • Andreas Waha - Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland; Universitätsklinikum Bonn, Department of Neuropathology, Bonn, Deutschland
  • Oliver Schnell - Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland
  • Ulrich Herrlinger - Universitätsklinikum Bonn, Klinik für Neurologie, Abteilung für klinische Neuroonkologie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland
  • Dieter Henrik Heiland - Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie. sine loco [digital], 06.-09.06.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocP139

doi: 10.3205/21dgnc427, urn:nbn:de:0183-21dgnc4276

Published: June 4, 2021

© 2021 Schneider et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objective: Glioblastoma cells assemble to a syncytial communicating network based on tumor microtubes (TMs) as ultra-long membrane protrusions. The relationship between network architecture and transcriptional profile remains poorly investigated. Drugs that interfere within this syncytial connectivity such as meclofenamate (MFA) may be highly attractive for glioblastoma therapy.

Methods: In a human neocortical slice model using glioblastoma cell populations of different transcriptional signatures, three-dimensional tumor networks were reconstructed and TM-based intercellular connectivity was mapped on the base of two-photon imaging data. MFA was used to modulate morphological and functional connectivity; downstream effects of MFA treatment were investigated by RNA sequencing and fluorescence-activated cell sorting (FACS) analysis.

Results: TM-based network morphology strongly differed between the transcriptional cellular subtypes of glioblastoma and was dependent on axon guidance molecule expression. MFA revealed both a functional and morphological demolishment of glioblastoma network architectures which was reflected by a reduction of TM-mediated intercellular cytosolic traffic as well as a breakdown of TM length. RNA sequencing confirmed a downregulation of NCAM and axon guidance molecule signaling upon MFA treatment. Loss of glioblastoma communicating networks was accompanied by a failure in the upregulation of genes that are required for DNA repair in response to TMZ-treatment and culminated in profound treatment response to TMZ-mediated toxicity.

Conclusion: The capacity of TM formation reflects transcriptional cellular heterogeneity. MFA effectively demolishes functional and morphological TM-based syncytial network architectures. These findings might pave the way to a clinical implementation of MFA as a TM-targeted therapeutic approach.