journal article
Open Access
Oct 11, 2023
GFAP serves as a structural element of tunneling nanotubes between glioblastoma cells and could play a role in the intercellular transfer of mitochondria
Abstract
Tunneling nanotubes (TNTs) are long F-actin-positive plasma membrane bridges connecting distant cells, allowing the intercellular transfer of cellular cargoes, and are found to be involved in glioblastoma (GBM) intercellular crosstalk. Glial fibrillary acid protein (GFAP) is a key intermediate filament protein of glial cells involved in cytoskeleton remodeling and linked to GBM progression. Whether GFAP plays a role in TNT structure and function in GBM is unknown. Here, analyzing F-actin and GFAP localization by laser-scan confocal microscopy followed by 3D reconstruction (3D-LSCM) and mitochondria dynamic by live-cell time-lapse fluorescence microscopy, we show the presence of GFAP in TNTs containing functional mitochondria connecting distant human GBM cells. Taking advantage of super-resolution 3D-LSCM, we show the presence of GFAP-positive TNT-like structures in resected human GBM as well. Using H2O2 or the pro-apoptotic toxin staurosporine (STS), we show that GFAP-positive TNTs strongly increase during oxidative stress and apoptosis in the GBM cell line. Culturing GBM cells with STS-treated GBM cells, we show that STS triggers the formation of GFAP-positive TNTs between them. Finally, we provide evidence that mitochondria co-localize with GFAP at the tip of close-ended GFAP-positive TNTs and inside receiving STS-GBM cells. Summarizing, here we found that GFAP is a structural component of TNTs generated by GBM cells, that GFAP-positive TNTs are upregulated in response to oxidative stress and pro-apoptotic stress, and that GFAP interacts with mitochondria during the intercellular transfer. These findings contribute to elucidate the molecular structure of TNTs generated by GBM cells, highlighting the structural role of GFAP in TNTs and suggesting a functional role of this intermediate filament component in the intercellular mitochondria transfer between GBM cells in response to pro-apoptotic stimuli.
Topics
No keywords indexed for this article. Browse by subject →
References
44
[1]
Ahmadipour "Does the expression of glial fibrillary acid protein (GFAP) stain in glioblastoma tissue have a prognostic impact on survival?" Neurochirurgie (2020) 10.1016/j.neuchi.2019.12.012
[2]
Belmokhtar "Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms" Oncogene (2001) 10.1038/sj.onc.1204436
[3]
Binda "Wnt5a drives an invasive phenotype in human glioblastoma stem-like cells" Cancer Res. (2017) 10.1158/0008-5472.can-16-1693
[4]
Broekman "Multidimensional communication in the microenvirons of glioblastoma" Nat. Rev. Neurol. (2018) 10.1038/s41582-018-0025-8
[5]
Pre-Clinical Drug Testing in 2D and 3D Human In Vitro Models of Glioblastoma Incorporating Non-Neoplastic Astrocytes: Tunneling Nano Tubules and Mitochondrial Transfer Modulates Cell Behavior and Therapeutic Response
Prospero Civita, Diana M. Leite, Geoffrey Pilkington
International Journal of Molecular Sciences
2019
10.3390/ijms20236017
[6]
Cordero Cervantes "Peering into tunneling nanotubes-The path forward" EMBO J. (2021) 10.15252/embj.2020105789
[7]
Escartin "Reactive astrocyte nomenclature, definitions, and future directions" Nat. Neurosci. (2021) 10.1038/s41593-020-00783-4
[8]
Galli "Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma" Cancer Res. (2004) 10.1158/0008-5472.can-04-1364
[9]
Gao "Mitochondria are dynamically transferring between human neural cells and alexander disease-associated GFAP mutations impair the astrocytic transfer" Front. Cell Neurosci. (2019) 10.3389/fncel.2019.00316
[10]
Ghorbani "Discovery of novel glioma serum biomarkers by proximity extension assay" Clin. Proteomics (2023) 10.1186/s12014-023-09400-5
[11]
Guichet "Asymmetric distribution of GFAP in glioma multipotent cells" PloS One (2016) 10.1371/journal.pone.0151274
[12]
Guttenplan "Astrocytes and microglia: models and tools" J. Exp. Med. (2019) 10.1084/jem.20180200
[13]
Huang "Revealing the structure and organization of intercellular tunneling nanotubes (TNTs) by STORM imaging" Nanoscale Adv. (2022) 10.1039/d2na00415a
[14]
Jansens "Pseudorabies virus US3-induced tunneling nanotubes contain stabilized microtubules, interact with neighboring cells via cadherins, and allow intercellular molecular communication" J. Virol. (2017) 10.1128/jvi.00749-17
[15]
Jung "Serum GFAP is a diagnostic marker for glioblastoma multiforme" Brain J. Neurol. (2007) 10.1093/brain/awm263
[16]
Kim "Mitochondrial dysfunction regulates the JAK-STAT pathway via LKB1-mediated AMPK activation ER-stress-independent manner" Biochem. Cell Biol. Biochim. Biol. Cell (2020) 10.1139/bcb-2019-0088
[17]
Kretschmer "Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer" Sci. Rep. (2019) 10.1038/s41598-019-44346-5
[18]
Liddelow "Reactive astrocytes: production, function, and therapeutic potential" Immunity (2017) 10.1016/j.immuni.2017.06.006
[19]
Moeton "GFAP isoforms control intermediate filament network dynamics, cell morphology, and focal adhesions" Cell Mol. Life Sci. CMLS (2016) 10.1007/s00018-016-2239-5
[20]
Olabarria "Disorders of astrocytes: alexander disease as a model" Annu. Rev. Pathol. (2017) 10.1146/annurev-pathol-052016-100218
[21]
Osswald "Brain tumour cells interconnect to a functional and resistant network" Nature (2015) 10.1038/nature16071
[22]
Ou "The role and therapeutic targeting of JAK/STAT signaling in glioblastoma" Cancers (2021) 10.3390/cancers13030437
[23]
Pinto "Tunneling nanotubes: the fuel of tumor progression?" Trends Cancer (2020) 10.1016/j.trecan.2020.04.012
[24]
Pinto "Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids" Biochem. J. (2021) 10.1042/bcj20200710
[25]
Roehlecke "Tunneling nanotubes and tumor microtubes in cancer" Cancers (2020) 10.3390/cancers12040857
[26]
Radu "GFAPδ: A promising biomarker and therapeutic target in glioblastoma" Front. Oncol. (2022) 10.3389/fonc.2022.859247
[27]
Raghavan "Oxidative stress and rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy" Cell Mol. Life Sci. (2022) 10.1007/s00018-021-04040-0
[28]
Resnik "Triple labelling of actin filaments, intermediate filaments and microtubules for broad application in cell biology: uncovering the cytoskeletal composition in tunneling nanotubes" Histochem Cell Biol. (2019) 10.1007/s00418-019-01806-3
[29]
Rustom "Nanotubular highways for intercellular organelle transport" Science (2004) 10.1126/science.1093133
[30]
Simone "AQP4-dependent glioma cell features affect the phenotype of surrounding cells via extracellular vesicles" Cell Biosci. (2022) 10.1186/s13578-022-00888-2
[31]
Sofroniew "Stem-cell-derived astrocytes divulge secrets of mutant GFAP" Cell Stem Cell (2018) 10.1016/j.stem.2018.10.020
[32]
Sommerlath "Molecular features of glioblastomas in long-term survivors compared to short-term survivors-a matched-pair analysis" Radiat. Oncol. Lond Engl. (2022) 10.1186/s13014-022-01984-w
[33]
Stassen "GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile" Oncotarget (2017) 10.18632/oncotarget.21540
[34]
Taiarol "The 3.0 cell communication: new insights in the usefulness of tunneling nanotubes for glioblastoma treatment" Cancers (2021) 10.3390/cancers13164001
[35]
Tichy "Prospective evaluation of serum glial fibrillary acidic protein (GFAP) as a diagnostic marker for glioblastoma" J. Neurooncol (2016) 10.1007/s11060-015-1978-8
[36]
Trivieri "Growth factor independence underpins a paroxysmal, aggressive Wnt5aHigh/EphA2Low phenotype in glioblastoma stem cells, conducive to experimental combinatorial therapy" J. Exp. Clin. Cancer Res. CR (2022) 10.1186/s13046-022-02333-1
[37]
Uceda-Castro "GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence" Sci. Rep. (2022) 10.1038/s41598-021-04127-5
[38]
Valdebenito "Tunneling nanotubes mediate adaptation of glioblastoma cells to temozolomide and ionizing radiation treatment" iScience (2020) 10.1016/j.isci.2020.101450
[39]
Valdebenito "Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions" Sci. Rep. (2021) 10.1038/s41598-021-93775-8
[40]
van Asperen "GFAP alternative splicing and the relevance for disease - a focus on diffuse gliomas" ASN Neuro (2022) 10.1177/17590914221102065
[41]
van Bodegraven "Importance of GFAP isoform-specific analyses in astrocytoma" Glia 10.1002/glia.23594
[42]
van Bodegraven "GFAP alternative splicing regulates glioma cell-ECM interaction in a DUSP4-dependent manner" FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 10.1096/fj.201900916r
[43]
van Bodegraven "GFAP alternative splicing regulates glioma cell–ECM interaction in a DUSP4‐dependent manner" FASEB J. 10.1096/fj.201900916r
[44]
Yadav "Clinical utility of serum glial fibrillary acidic protein in glial neoplasm" Surg. Neurol. Int. (2022) 10.25259/sni_889_2022
Metrics
26
Citations
44
References
Details
- Published
- Oct 11, 2023
- Vol/Issue
- 11
- License
- View
Authors
Cite This Article
L. Simone, D. L. Capobianco, F. Di Palma, et al. (2023). GFAP serves as a structural element of tunneling nanotubes between glioblastoma cells and could play a role in the intercellular transfer of mitochondria. Frontiers in Cell and Developmental Biology, 11. https://doi.org/10.3389/fcell.2023.1221671
Related
You May Also Like
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Ruchi Kumari, Parmjit Jat · 2021
1,362 citations
CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of Progression and Metastasis of Cancer Cells
Linda T. Senbanjo, Meenakshi A. Chellaiah · 2017
712 citations
Exosome-Based Cell-Cell Communication in the Tumor Microenvironment
Joana Maia, Sergio Caja · 2018
593 citations
In vitro Cell Migration, Invasion, and Adhesion Assays: From Cell Imaging to Data Analysis
Jordi Pijuan, Carla Barceló · 2019
491 citations
Feeling Stress: The Mechanics of Cancer Progression and Aggression
Josette M. Northcott, Ivory S. Dean · 2018
368 citations