End-binding 1 protein overexpression correlates with glioblastoma progression and sensitizes toVinca-alkaloidsin vitroandin vivo

Bergès, Raphaël; Baeza-Kallee, Nathalie; Tabouret, Émeline; Chinot, Olivier; Petit, Marie; Kruczynski, Anna; Figarella‐Branger, Dominique; Honoré, Stéphane; Braguer, Diane

doi:10.18632/oncotarget.2646

Cited by 29 publications

(51 citation statements)

References 46 publications

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“…Furthermore, EB1 overexpression correlated with glioblastoma progression and migratory potential, whereas downregulation of EB1 by shRNA inhibited cell migration and proliferation in vitro [52]. Modulation of γ-actin expression leads to similar functional changes in normal [53] and neoplastic cells [23, 27, 54].…”

Section: Discussionmentioning

confidence: 99%

Interaction of microtubules with the actin cytoskeleton via cross-talk of EB1-containing +TIPs and γ-actin in epithelial cells

et al. 2016

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Actin microfilaments and microtubules are both highly dynamic cytoskeleton components implicated in a wide range of intracellular processes as well as cell-cell and cell-substrate interactions. The interactions of actin filaments with the microtubule system play an important role in the assembly and maintenance of 3D cell structure. Here we demonstrate that cytoplasmic actins are differentially distributed in relation to the microtubule system. LSM, 3D-SIM, proximity ligation assay (PLA) and co-immunoprecipitation methods applied in combination with selective depletion of β- or γ-cytoplasmic actins revealed a selective interaction between microtubules and γ-, but not β-cytoplasmic actin via the microtubule +TIPs protein EB1. EB1-positive comet distribution analysis and quantification have shown more effective microtubule growth in the absence of β-actin. Our data represent the first demonstration that microtubule +TIPs protein EB1 interacts mainly with γ-cytoplasmic actin in epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Interaction of microtubules with the actin cytoskeleton via cross-talk of EB1-containing +TIPs and γ-actin in epithelial cells

et al. 2016

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“…(phase IIA) or oral (phase I) administration (18)(19)(20). Previously, we reported that microtubule þ End-binding 1-protein (EB1) was a factor of bad prognosis in glioblastoma, and that Vinca-alkaloid chemotherapy could improve the treatment of glioblastoma patients with an EB1-overexpressing tumor (21). We demonstrated notably the EB1-dependent migratory potential of two human primary glioblastoma CSLCs, GBM6 and GBM9, established from sorted A2B5 þ cells (22).…”

Section: Introductionmentioning

confidence: 90%

“…ShRNA plasmid that specifically knocked out human EB1 (NM_012325) and negative shRNA control plasmid (Mission non-target shRNA control vector) were obtained from Sigma-Aldrich. Cells were transfected according to the protocol previously described (21). Stable GFP-shRNA-transfected cells were obtained after transfection with peGFP-N3 vector (Clontech) using lipofectamineTM 2000 system (Invitrogen) and selection with 0.6 mg/mL geneticin (Life Technologies).…”

Section: Cell Transfectionsmentioning

confidence: 99%

The Novel Tubulin-Binding Checkpoint Activator BAL101553 Inhibits EB1-Dependent Migration and Invasion and Promotes Differentiation of Glioblastoma Stem-like Cells

Bergès

Tchoghandjian

Honoré

et al. 2016

Molecular Cancer Therapeutics

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Glioblastoma patients have limited treatment options. Cancer stem-like cells (CSLC) contribute to glioblastoma invasiveness and repopulation; hence, they represent promising targets for novel therapies. BAL101553 is a prodrug of BAL27862, a novel microtubule-destabilizing agent inhibiting tumor cell proliferation through activation of the spindle assembly checkpoint, which is currently in phase I/II clinical development. Broad anticancer activity has been demonstrated against human cancer models, including tumors refractory to conventional treatments. We have shown that overexpression of microtubule + end-binding 1-protein (EB1) correlates with glioblastoma progression and poor survival. Here, we show that BAL27862 inhibits the growth of two glioblastoma CSLCs. As EB1 is overexpressed in the CSLC line GBM6, which displays a high tumorigenicity and infiltrative pattern of migration in vivo, we investigated drug activity on GBM6 according to EB1 expression. BAL27862 inhibited migration and colony formation at subcytotoxic concentrations in EB1-expressing control cells (GBM6-sh0) but only at cytotoxic concentrations in EB1-downregulated (GBM-shE1) cells. Three administrations of BAL101553 were sufficient to provoke an EB1-dependent survival benefit in tumor-bearing mice. Patterns of invasion and quantification of tumor cells in brain demonstrated that GBM6-sh0 cells were more invasive than GBM6-shEB1 cells, and that the antiproliferative and anti-invasive effects of BAL101553 were more potent in mice bearing control tumors than in EB1-downregulated tumors. This was associated with inhibition of stem cell properties in the GBM6-sh0 model. Finally, BAL27862 triggered astrocytic differentiation of GBM6 in an EB1-dependent manner. These results support the potential of BAL101553 for glioblastoma treatment, with EB1 expression as a predictive biomarker of response. Mol Cancer Ther; 15(11); 2740-9. ©2016 AACR.

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“…Several studies reported their localization in TM membrane (32,33), especially for MMP-2 and MT1-MMP.Our interest arises from the analysis of the role of TMs in tumor progression and of the effect of different drugs on their structures and dynamics (34,35). The inhibition of TMs leads to a decrease in cell migration and proliferation, with obvious consequences on GB treatment (34)(35)(36). The process of growth and retraction of TMs plays a fundamental role for cell-to-cell communication routing (17,18,(20)(21)(22)(23), as well as a transient binding platform for essential proteins that regulate tumor dynamics (37).…”

mentioning

confidence: 99%

“…The process of growth and retraction of TMs plays a fundamental role for cell-to-cell communication routing (17,18,(20)(21)(22)(23), as well as a transient binding platform for essential proteins that regulate tumor dynamics (37). Among these proteins, the presence of microtubule plus end-binding protein EB1 correlates with GB progression and poor survival (36,38). This has led to a great interest in the development of drugs aimed at affecting end-binding proteins expression and, consequently, TM dynamics (35).…”

mentioning

confidence: 99%

Modeling invasion patterns in the glioblastoma battlefield

Conte

Casas‐Tintó

Soler

2020

Preprint

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and infiltration in uncontaminated brain regions. We propose a novel multidisciplinary approach, based on in vivo experiments in Drosophila and mathematical models, for the proteins dynamics at the front of Glioblastoma, with a predictive value of the tumor progression.feedback with an evolutionary mathematical model that predicts behaviors and interactions of these biological agents.GB in Drosophila The most frequent genetic lesions in GB include the constitutive activation of phosphatidylinositol 3-kinase (PI3K) and Epidermal Growth Factor Receptor (EGFR) pathways, which drive cellular proliferation and tumor malignancy (10). Drosophila melanogaster has emerged as one of the most reliable animal models for GB; it is based on equivalent genetic mutations in EGFR and PI3K pathways found in patients (11). Glial cells respond to this oncogenic transformation and reproduce all main features of the disease, including glial expansion and invasion, but in a shorter period of time. This Drosophila model has been used for drug and genetic screenings and the results have been validated in human GB cells (REFs) (12)(13)(14).Agents involved in the battlefield GB growth and migration are driven by specific signaling pathways as well as interactions between the tumor and its extracellular microenvironment. In our study, we include the cell membrane protrusions (TMs) as driving factors of tumor progression, as well as cell response to signaling gradients and the interplay with the Extra Cellular Matrix (ECM). A schematic diagram of the described dynamics is given in Figure 1.The dynamics of tumor cell membrane, including cell protrusions, is fundamental in several processes, among others cell movements, cell transport, and exposure to molecular interactions with substrates during GB progression. Generally, cell protrusions are highly dynamic extensions of the plasma membrane that are involved in cell migration and invasion through the ECM.Different types of protrusions have been identified to contribute to cell spreading, depending on specific contexts, cell types, and microenvironment. In particular, filopodia are thin, finger-like and highly dynamic membrane protrusions that have a significant role in mediating intercellular communication and in modulating cell adhesion. They appear to be required for haptotaxis and chemotaxis (15), i.e., for the cell response to the gradient of insoluble (haptotaxis) and soluble Proteases are enzymes that catalyze the breakdown of proteins into smaller polypeptides or single amino acids. Some type of proteases are localized around the cell membrane and play a key role in promoting tumor invasion and tissue remodeling. They induce proteolysis of ECM components (29) and maintain a microenvironment that facilitates tumor cell survival. Protease profiling studies have indicated that the expression of serine proteases, cysteine proteases and matrix metalloproteases (MMPs), the most prominent family of proteinases associated with tumorigenesis, increase in high-grade astrocytoma compared with nor...

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End-binding 1 protein overexpression correlates with glioblastoma progression and sensitizes toVinca-alkaloidsin vitroandin vivo

Cited by 29 publications

References 46 publications

Interaction of microtubules with the actin cytoskeleton via cross-talk of EB1-containing +TIPs and γ-actin in epithelial cells

Interaction of microtubules with the actin cytoskeleton via cross-talk of EB1-containing +TIPs and γ-actin in epithelial cells

The Novel Tubulin-Binding Checkpoint Activator BAL101553 Inhibits EB1-Dependent Migration and Invasion and Promotes Differentiation of Glioblastoma Stem-like Cells

Modeling invasion patterns in the glioblastoma battlefield

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