Meclofenamate causes loss of cellular tethering and decoupling of functional networks in glioblastoma.
glioblastoma
intercellular network architecture
meclofenamate
tumor microtubes
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
02 11 2021
02 11 2021
Historique:
pubmed:
18
4
2021
medline:
6
11
2021
entrez:
17
4
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33864086
pii: 6231712
doi: 10.1093/neuonc/noab092
pmc: PMC8563322
doi:
Substances chimiques
Meclofenamic Acid
48I5LU4ZWD
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1885-1897Commentaires et corrections
Type : CommentIn
Informations de 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: journals.permissions@oup.com.
Références
Biomaterials. 2009 Oct;30(29):5572-82
pubmed: 19643471
Oncogene. 2009 Oct 8;28(40):3537-50
pubmed: 19684614
Nature. 2019 Sep;573(7775):532-538
pubmed: 31534219
Int J Cancer. 2020 Dec 15;147(12):3281-3291
pubmed: 32510582
Int J Cancer. 2016 Apr 1;138(7):1709-18
pubmed: 26519239
Annu Rev Cell Dev Biol. 2006;22:287-309
pubmed: 16824016
J Biol Chem. 2013 Jan 25;288(4):2210-22
pubmed: 23195957
Cell Death Differ. 2005 Aug;12(8):1044-56
pubmed: 16015381
Nat Rev Clin Oncol. 2018 Feb;15(2):81-94
pubmed: 29115304
N Engl J Med. 2014 Feb 20;370(8):699-708
pubmed: 24552317
Cell. 2019 Aug 8;178(4):835-849.e21
pubmed: 31327527
Nat Immunol. 2018 Mar;19(3):206
pubmed: 29476180
JAMA. 2017 Dec 19;318(23):2306-2316
pubmed: 29260225
Neuro Oncol. 2017 Oct 1;19(10):1316-1326
pubmed: 28419303
Life Sci Alliance. 2019 Jun 27;2(4):
pubmed: 31249133
Nature. 2014 May 8;509(7499):189-94
pubmed: 24776795
Dev Cell. 2010 Jun 15;18(6):884-901
pubmed: 20627072
Hum Exp Toxicol. 2013 Nov;32(11):1164-9
pubmed: 23584353
Cancers (Basel). 2019 Jun 20;11(6):
pubmed: 31226836
Oncogene. 2008 Sep 4;27(39):5169-81
pubmed: 18469856
Curr Neuropharmacol. 2016;14(7):759-71
pubmed: 27262601
Nature. 2015 Dec 3;528(7580):93-8
pubmed: 26536111
Cold Spring Harb Symp Quant Biol. 2005;70:343-56
pubmed: 16869771
Clin Cancer Res. 2009 Jul 15;15(14):4622-9
pubmed: 19584161
Pharmaceuticals (Basel). 2021 Feb 27;14(3):
pubmed: 33673490
Bioinformatics. 2011 Sep 1;27(17):2453-4
pubmed: 21727141
Nature. 2019 Sep;573(7775):539-545
pubmed: 31534222
Pharmacology. 1984;29(2):85-93
pubmed: 6433367
Neuro Oncol. 2021 May 5;23(5):757-769
pubmed: 33320195
Dev Biol. 2003 Jun 15;258(2):364-84
pubmed: 12798294
Nature. 2016 May 18;533(7604):493-498
pubmed: 27225120
Lancet. 2019 Feb 16;393(10172):678-688
pubmed: 30782343
Gene Expr Patterns. 2003 Jun;3(3):279-83
pubmed: 12799072
Nat Rev Mol Cell Biol. 2007 Apr;8(4):296-306
pubmed: 17356579
J Neurosci. 2002 May 1;22(9):3568-79
pubmed: 11978833
Nat Commun. 2019 Jun 11;10(1):2541
pubmed: 31186414
Mol Cancer Res. 2018 Apr;16(4):655-668
pubmed: 29330292
N Engl J Med. 2005 Mar 10;352(10):987-96
pubmed: 15758009
N Engl J Med. 2014 Feb 20;370(8):709-22
pubmed: 24552318