Clemastine suppresses proneural glioblastoma stem cell growth
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ABSTRACT:
PROVIDER: PRJNA773389 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16520941_1.fastq.gz | Fastqsanger.gz | |||
| SRR16520941_2.fastq.gz | Fastqsanger.gz | |||
| SRR16520942_1.fastq.gz | Fastqsanger.gz | |||
| SRR16520942_2.fastq.gz | Fastqsanger.gz | |||
| SRR16520943_1.fastq.gz | Fastqsanger.gz |
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Project description:Clemastine suppresses proneural glioblastoma stem cell growth II
| PRJNA773719 | ENA
Project description:Glioblastoma (GBM) cells’ stemness-like features and lineage plasticity promote tumor progression. Here, we demonstrate that Clemastine, a drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary GBM cultures bearing PDGFRA amplification. We show that these effects of GBM cells were accompanied by altered gene expression profiling indicative of a more differentiated state of tumor cells, in resonating with Clemastine’s activity in promoting the differentiation of normal oligodendrocyte progenitors (OPCs) into mature oligodendrocyte. Functional assays for proteins that can be pharmacologically targeted by Clemastine, including histamine receptors, muscarinic receptors, and Emopamil binding protein (EBP), revealed the essential roles of these proteins in sustaining GBM cell propagation and suggested that Clemastine likely impairs tumor cells via targeting multiple pathways. Finally, we showed that a PDGFB-driven mouse glioma model, representing the proneural subtype GBMs, was similarly susceptible to Clemastine treatment. Collectively, these results identify pathways that are essential for maintaining the proneural progenitor features of GBMs, and suggest that non-oncology, low toxicity drugs with OPC differentiation promoting effects, such as Clemastine, can be exploited for targeting GBM cell’s progenitor property.
2023-10-04 | GSE186319 | GEO
Project description:Glioblastoma (GBM) cells’ stemness-like features and lineage plasticity promote tumor progression. Here, we demonstrate that Clemastine, a drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary GBM cultures bearing PDGFRA amplification. We show that these effects of GBM cells were accompanied by altered gene expression profiling indicative of a more differentiated state of tumor cells, in resonating with Clemastine’s activity in promoting the differentiation of normal oligodendrocyte progenitors (OPCs) into mature oligodendrocyte. Functional assays for proteins that can be pharmacologically targeted by Clemastine, including histamine receptors, muscarinic receptors, and Emopamil binding protein (EBP), revealed the essential roles of these proteins in sustaining GBM cell propagation and suggested that Clemastine likely impairs tumor cells via targeting multiple pathways. Finally, we showed that a PDGFB-driven mouse glioma model, representing the proneural subtype GBMs, was similarly susceptible to Clemastine treatment. Collectively, these results identify pathways that are essential for maintaining the proneural progenitor features of GBMs, and suggest that non-oncology, low toxicity drugs with OPC differentiation promoting effects, such as Clemastine, can be exploited for targeting GBM cell’s progenitor property.
2023-10-04 | GSE186392 | GEO
Project description:Glioblastoma multiforme (GBM) is an aggressive, heterogeneous and highly vascularized brain tumor. GBM is thought to arise from glioblastoma stem-like cells (GSCs) which are characterized as being either proneural or mesenchymal. The former isolates of GSCs are tight sphere forming and slow growing while mesenchymal GSCs are lose sphere forming, fast growing, highly invasive and when dominant yield poorer patient prognosis. GSCs are known to be plastic in nature and can therefore evolve from a proneural to a mesenchymal state. Here, we observed that factors secreted by endothelial cells (which make up the brain vasculature) alter several properties of GSCs resulting in the acquisition of a more mesenchymal and invasive phenotype coupled with changes at the level of secretory and cellular proteome. Thus, using mass spectrometry, quantitative proteomic analysis and GO term filters, we identified several mesenchymal traits in proneural GSCs exposed to endothelial cell secretome. Specifically, proneural cells treated with the conditioned media derived from human umbilical vein endothelial cells (HUVEC) upregulated the expression of mesenchymal proteins such as CD44 and VIM, while downregulating the expression of the proneural proteins such as NOTCH1, activated NOTCH intracellular domain (NICD), SOX2 and NESTIN, which were validated using flow cytometry (FACS) and western blots (WB). Using DAVID analysis tool, we detected the features of cellular proteome indicative of the activation of NFkB, Wnt and several other pathways in the proneural cells treated with HUVEC conditioned media. Using conditioned media fractionation through several centrifugation steps we identified the extracellular vesicles (EV) sedimented at 100,000 x g using ultracentrifugation, as the source of activity in endothelial conditioned media capable of triggering mesenchymal shift in proneural GSCs. EVs are heterogeneous membrane structures containing multiple bioactive macromolecules, which have the ability to carry multiple bioactive proteins, transfer them to recipient cells and alter their function, signalling and biological programmes. We compared the effects of EVs, soluble fraction and unfractionated conditioned media in terms of their ability to trigger mesenchymal changes in the phenotype of proneural GSCs. Once the cultures were established, the culture medium was removed and replaced with HUVEC-derived material (conditioned media, supernatant or EV fraction) and responses evaluated over 7 days by microscopical analysis of sphere structures, and biochemically by following the aforementioned proneural or mesenchymal markers (WB, FACS). We observed an upregulation of mesenchymal proteins, as well as downregulation of the proneural proteins, mentioned above. These effects recapitulated those of unfractionated conditioned media and were absent from target cells exposed to EV-depleted conditioned media. The data analysis of EV proteome included canonical markers and pathways of cellular vesiculation as well as markers and pathways of interest with regards to the biological effects associated with treatment of GSC recipient cells. In this regard we observed several EV related tetraspanin markers, which were validated using western blot including CD9, CD63, CD81 and a purity control, BIP. Although we identified several potential effectors associated with endothelial cell EVs that could impact proneural cell phenotype, we focused on MMPs for at least three reasons: (i) evidence in the literature (see text) indicated that MMPs may induce differentiation programs in neural stem cells; (ii) MMPs in EV cargo were relatively abundant and have been implicated in various biological processes; (iii) MMPs released from endothelial cells could be functionally involved in disrupting proneural cell sphere structures that we observed in the presence of endothelial cell secretome. We noted the expressions of MMP1, MMP2, MMP11 and MP14 in our HUVEC-EV mass spectrometry dataset, the activity of which was validated using the MMP activity assay kit from abcam (ab112146). Using GO terms we also detected a signal for NFkB pathway activation in the proteome of endothelial (HUVEC) conditioned media-treated proneural GSCs. NFkB activation is regarded as hallmark of mesenchymal phenotype in GSCs and GBM cells. We validated that the upregulation of NFkB, was also true for the proneural cells treated with HUVEC derived EVs. Moreover, upon blocking MMP expression in proneural cells treated with endothelial cell EVs, we inhibited the activation of NFkB activity thereby documenting that the initial effects of MMPs trigger a shift in cellular phenotype toward NfkB activation and mesenchymal reprogramming. Briefly, we compared GO terms of GSC157 cells treated with their own or HUVEC-derived EVs. Validation of the NFkB pathway activation was analysed using WB and immunofluorescence for levels of NFkB and phosphor-NFkB.
2022-10-14 | PXD034819 | Pride
Project description:To identify proneural, neural, classical and mesenchymal gene expression signature (Verhaak's classification) in human glioblastoma, a microarray analysis on 16 patient-derived glioblastoma stem cell cultures was performed.
2018-06-26 | E-MTAB-6408 | biostudies-arrayexpress
Project description:Gene expression profile of murine proneural glioblastoma
| PRJNA716179 | ENA
Project description:Glycoproteomic screening indicates that core fucosylation activation is more highly enhancedin mesenchymal (MES) than in proneural (PN) glioblastoma cancer stem cells (GSCs) and this pattern is retained in subgroup-specific xenograftsand human patients’ samples. Most MES-restricted core fucosylated proteins are involved in therapeutically relevant pathological processes, such as extracellular matrix interaction and tumor invasion.
2022-11-09 | PXD033408 | Pride
Project description:Prognosis of glioblastoma remains poor despite a great deal of research. In glioblastoma, the existence of glioblastoma stem cells (GSCs) has been shown, which are responsible for tumorigenesis, invasive capacity, and therapy resistance. One of cancer stem cell markers, Leucine-rich repeat-containing G-protein coupled receptor (Lgr5) plays a role in maintenance of GSCs, however, properties of the Lgr5 positive GSCs have not been fully understood. We applied the Sleeping-Beauty transposon-induced glioblastoma model to the Lgr5-GFP transgenic mice and sorted the GFP-positive cells from the neurosphere cultures derived from the mouse glioblastoma tissues. We found that the GFP-positive GSCs exhibited higher expression of Gli2 using a global gene expression analysis. Gli2 knockdown using lentiviral-mediated shRNA downregulates both the Hedgehog- and Wnt signaling pathway-related genes including Lgr5, suppresses tumor cell proliferation and invasion capacity, and induces apoptosis. Pharmacological Gli inhibition by GANT61 also suppresses tumor cell proliferation. Furthermore, the orthotopic transplantation model revealed that silencing of Gli2 suppresses tumorigenicity of GSCs in vivo. These findings demonstrate that Gli2 affects not only Hh pathway but also Wnt pathway and plays an important role in the GSC maintenance, suggesting that Gli2 may be a potential therapeutic target for glioblastoma treatment.
2020-08-20 | GSE156522 | GEO
Project description:SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. Gene expression data for 17 isolated Glioma Stem Cells
2013-08-15 | E-GEOD-49161 | biostudies-arrayexpress
Project description:Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSC), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms which drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore mandatory. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that employed in the clinical setting, mesenchymal GSCs turned out to be dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA-damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes
2021-06-30 | GSE178260 | GEO