Meclofenamate causes loss of cellular tethering and decoupling of functional networks in glioblastoma.

Abstract

BACKGROUND:

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 with 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 basis 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 temozolomide (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.

• Authors: Matthias Schneider, Lea Vollmer, Anna-Laura Potthoff, Vidhya M Ravi, Bernd O Evert, Mohummad A Rahman, Shahin Sarowar, Jan Kueckelhaus, Paulina Will, David Zurhorst, Kevin Joseph, Julian P Maier, Nicolas Neidert, Paolo d'Errico, Melanie Meyer-Luehmann, Ulrich G Hofmann, Andreas Dolf, Paolo Salomoni, Erdem Güresir, Per Ø Enger, Martha Chekenya, Torsten Pietsch, Patrick Schuss, Oliver Schnell, Mike-Andrew Westhoff, Jürgen Beck, Hartmut Vatter, Andreas Waha, Ulrich Herrlinger, Dieter H Heiland
• Journal: Neuro-oncology (Neuro Oncol) Vol. 23 Issue 11 Pg. 1885-1897 (11 02 2021) ISSN: 1523-5866 [Electronic] England
• PMID: 33864086 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Meclofenamic Acid

Topics

• Brain Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation
• Glioblastoma (drug therapy)
• Humans
• In Vitro Techniques
• Meclofenamic Acid (pharmacology)