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Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial in vivo intracranial transplantation

ABSTRACT: One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, considered a potential cause of tumor recurrence. Infiltrated GBM cells are difficult to completely eradicate surgically and with local therapeutic modalities. Although much effort has focused on understanding the various mechanisms controlling GBM invasiveness, the nature of the invasiveness remains poorly characterized. Here, we established a highly invasive glioma cell line (U87MGR2/R3 cells) and a non-invasive cell line (U87MGL2/L3 cells) from U87MG glioma cells following four rounds of serial in vivo intracranial transplantation. Compared to U87MGL2/L3 cells, U87MGR2/R3 cells were highly invasive and had glioma stem cell-like properties. Microarray analysis showed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated, whereas several cancer stem cell-relevant genes (Wnt10A, Frizzled 4, and CD44) were upregulated in U87MGR2/R3 cells compared to U87MGL2/L3 cells. U87MGR2/R3 cells were resistant to anticancer drug-induced cell death, which was partially due to downregulation of caspase3 and PDCD4. U87MGR2/R3 cells retained activated Wnt/β-catenin signaling through Frizzled 4, which was sufficient to control neurosphere formation. In addition, Frizzled 4 promoted expression of the epithelial to mesenchymal transition regulator, SNAI1, and acquisition of a mesenchymal phenotype. Taken together, our results indicate that Frizzled 4 may be a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and may be a major cause of GBM recurrence and poor prognosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21570 | GEO | 2010/04/29

SECONDARY ACCESSION(S): PRJNA127005

REPOSITORIES: GEO

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Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial in vivo intracranial transplantation

Project description:One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, considered a potential cause of tumor recurrence. Infiltrated GBM cells are difficult to completely eradicate surgically and with local therapeutic modalities. Although much effort has focused on understanding the various mechanisms controlling GBM invasiveness, the nature of the invasiveness remains poorly characterized. Here, we established a highly invasive glioma cell line (U87R4 cells) and a non-invasive cell line (U87L4 cells) from U87MG glioma cells following four rounds of serial in vivo intracranial transplantation. Compared to U87L4 cells, U87R4 cells were highly invasive and had glioma stem cell-like properties. Microarray analysis showed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated, whereas several cancer stem cell-relevant genes (Wnt10A, Frizzled 4, and CD44) were upregulated in U87R4 cells compared to U87L4 cells. U87R4 cells were resistant to anticancer drug-induced cell death, which was partially due to downregulation of caspase3 and PDCD4. U87R4 cells retained activated Wnt/Î²-catenin signaling through Frizzled 4, which was sufficient to control neurosphere formation. In addition, Frizzled 4 promoted expression of the epithelial to mesenchymal transition regulator, SNAI1, and acquisition of a mesenchymal phenotype. Taken together, our results indicate that Frizzled 4 may be a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and may be a major cause of GBM recurrence and poor prognosis. We established a highly invasive glioma cell line (U87R4 cells) and a non-invasive cell line (U87L4 cells) from U87MG glioma cells following four rounds of serial in vivo intracranial transplantation to characterize the mRNA expression profile of highly invasive glioma cells compared to non-invasive/parental glioma cell lines.

2010-05-27 | E-GEOD-21570 | biostudies-arrayexpress

U87_Radio_Resistance_Invasive_Noninvasive

Project description:Background: Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy is together with surgery the mainstay treatment in management of patients with GBM, however, infiltrative growth pattern and radioresistance of glioma cells impedes therapeutic effects. Our study sought to investigate 1) whether GBM invasive cells render them resistant to radiotherapy and 2) what are the potential molecular mechanisms underlying the radioresistance via gene expression profiling. <br>Procedures: In-vitro selection of invasive cells using matrigel-coated transwell assay: U87 cells were starved 8h prior to seeding. 5x105 cells in 2 mL serum-free DMEM medium were plated in the upper transwell inserts of a 6-well Boydem chamber. 10% FCS was added in the medium of the lower chamber. After 20h incubation, non-invasive cells on the surface of the membrane were scratched and recovered. Invasive cells migrating through matrigel due to the gradient of attractant were recovered by trypsin/EDTA after the membrane was washed with PBS twice and swabbed by cotton tips. Evaluate the invasiveness of selected phenotype of U87 cells by time-lapse wound-healing assay: 5x104 cells in 100μL serum-free DMEM medium were seeded in a 96-well ImageLock plate with each well was pre-coated with matrigel. Wounds were scratched using a 96-pin WoundMaker and gently washed with 2xPBS. After cooling equilibration, the wounds were coated with a second layer of matrigel. The microplate was incubated at 37oC and 5% CO2 for 30min. Cell invasion was recorded by living-image microscopy over 48h. Microarray: after confirmation of enhanced invasive ability, invasive and non-invasive cell populations were used for RNA isolation, cDNA transcription, and chip hybridization.

2023-11-08 | E-MTAB-4608 | biostudies-arrayexpress

CHRM3 is a novel prognostic factor of poor prognosis and promotes GBM progression via activation of oncogenic invasive growth factors

Project description:Glioblastoma (GBM) is the most aggressive cancer in brain and contains a high mortality ratedue to lack of effective treatment strategy. Molecular mechanisms of GBM characteristic invasive growth are urgently need to improve the poor prognosis. Via single nuclear-sequences of primary and recurrent GBM samples, level of the M3 muscarinic acetylcholine receptor (CHRM3) was significantly higher in recurrent samples. Moreover, immunohistochemical staining of an array of glioma samples showed that high levels of CHRM3 is correlated to poor prognosis of glioma, consistent with The Cancer Genome Atlas (TCGA) database. Knockdown of CHRM3 retarded glioma cell growth and invasion. In vivo assay of orthotopic glioma animal model indicated that inhibition of CHRM3 significantly suppressed glioma progression with prolonged survival time. Transcriptome analysis revealed that CHRM3 knockdown significantly reduced array of classic factors involved in cancer invasive growth including MMP1/MMP3/MMP10/MMP12 and CXCL1/CXCL5/CXCL8. Taken together, our study identified that CHRM3 is a new and important factor of GBM progression via regulation of multiple oncogenic genes and these results provide a new biomarker for prognosis and therapy of GBM patients.

2022-12-10 | GSE220083 | GEO

Expression data from U87 glioma cells and U87-2M1 glioma cells

Project description:An experimental lung metastasis assay was used to derive an invasive subline of U87 that is metastatic in mice. We used microarray analyses to find out over-represented gene ontologies that can explain the observed enhanced invasiveness of U87-2M1 cells. Early passage U87-2M1 cells and parental U87 glioma cells from ATCC were selected for RNA extraction and hybridization on microarray

2012-12-31 | E-GEOD-35169 | biostudies-arrayexpress

Homo sapiens

Project description:Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial in vivo intracranial transplantation

| PRJNA127005 | ENA

Gene Fusion Discovery through RNA Sequencing of Human Glioblastoma Stem Cell Lines

Project description:<p>We used massively parallel, paired-end sequencing of expressed transcripts (RNA-seq) to detect novel gene fusions in short-term cultures of glioma stem-like cells freshly isolated from nine patients carrying primary glioblastoma multiforme (GBM). The culture of primary GBM tumors under serum-free conditions selects cells that retain phenotypes and genotypes closely mirroring primary tumor profiles as compared to serum-cultured glioma cell lines that have largely lost their developmental identities.</p>

| phs000505 | dbGaP

MiR-21 Promotes Glioma Invasion by Targeting MMP Regulators.

Project description:Substantial data indicate that microRNA-21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This miRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including RECK and TIMP3, suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense olgonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of glioma in nude mice. Moreover, down-regulation of miR-21 in glioma cells leads to decrease of their migratory and invasion abilities. Our data suggest that miR-21 contributes to the glioma malignancy by down-regulation of MMP inhibitors that leads to activation of MMPs thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir like miR-21 with specific antisense molecules can provide a novel therapeutic approach for “physiological” modulation of multiple proteins whose expression is de-regulated in cancer.

2008-07-12 | GSE11778 | GEO

Systematic identification of molecular pathways driving GBM invasion

Project description:Glioblastoma multiforme (GBM) is the most prevalent and deadliest adult brain tumor. To systematically characterize the pathways governing brain invasion, we developed a three-dimensional (3D) ex vivo organotypic invasion model with clinical relevance to GBM. We used this model to enrich for highly invasive GBM cell population. Using next-generation sequencing to transcriptomically profile highly invasive and poorly invasive GBM cell populations, we have identified a network of extracellular matrix (ECM) components, including multiple collagens and collagen-interacting proteins, which are upregulated by invading GBM cells and strongly correlate in expression with clinical glioma progression outcomes. We identify the interferon regulatory factor 3 (IRF3) as a direct transcriptional repressor of ECM factors in GBM and show that IRF3 acts as an endogenous suppressor of GBM invasion. Therapeutic activation of IRF3 by inhibiting casein kinase 2 (CK2) -- a negative regulator of IRF3 phosphorylation -- downregulated the expression of ECM factors and suppressed GBM invasion in ex vivo and in vivo models across a panel of patient-derived GBM cell lines representative of the main molecular GBM subtypes in the clinic. Our findings illustrate an integrated and systematic approach for the discovery of novel pathways regulating brain tumor invasion and provide a strong mechanistic insight into the notorious, yet poorly understood, invasion capacity of GBM tumors.

2017-10-01 | GSE87535 | GEO

Identification of novel genes associated with human glioblastoma (GBM) tumor-initiating cells (TICs)

Project description:Most patients affected by Glioblastoma multiforme (GBM) experience a recurrence of the disease because of the spreading of tumor-initiating cells (TICs) beyond surgical boundary. Unveiling and targeting molecular mechanisms causing this process is a logic goal to impair GBM killing ability. In an orthotopic xenograph model, we have noticed that GBM TICs isolated from several patients may fall into two classes of invasive behavior: nodular or diffuse. In order to identify genes responsible for the diffusive type of invasion, we have compared by genome expression analysis, cultured GBM TICs belonging to the two classes. This analysis allowed us to identify a small group of regulated genes in the diffusive type of GBM TICs. The gene ontology process of cell adhesion and the localization of the gene product functions to the plasmamembrane resulted significantly associated to this gene set. Real time RT-PCR and immunofluorescence analyses performed for a selected subgroup of regulated genes/gene products confirmed the results obtained by the expression analysis. Some of the genes that we found upregulated in our screening were already proven to be involved in Glioma cell invasion supporting our study. However, we have also identified genes that were not previously implicated in this process. To assess whether these are required to sustain TICs GBM invasion, we silenced a subset of them and evaluated in Boyden chamber the invasive ability of the cells. Our study provides novel target genes to be evaluated for the inhibition of GBM diffusion within the SNC. As we observed that GBM TICs may fall into two classes of M-bM-^@M-^\in vivoM-bM-^@M-^] invasive behavior in mouse orthotopic transplantation: expansive or highly diffusive, resulting in the hostM-bM-^@M-^Ys white and gray matters substitution, we decided to identify genes associated with the latter phenotype by microarray analysis. Three replicates of each class were analyzed.

2012-09-11 | E-GEOD-16805 | biostudies-arrayexpress

Chip-seq data of BV2 cells by anti-Nr4a2 antibody

Project description:Glioma is the most common type of intracranial tumor and accounts for 75% of malignant brain tumors. Glioblastoma (GBM) is the most malignant form of glioma, with strong invasive capabilities and a high relapse rate even after treatment. Here, our RNA seqencing analysis of BV2 cells treated by H2O2 and si-Nr4a2 reveal the effect of oxdiative stress and Nr4a2-knockdown on phenotype of microglia. Chip-seqencing andlysis of BV2 cells by anti-Nr4a2 antibody is to find the target genes regulated by Nr4a2. Overall, our results reveal that Nr4a2 as the major transcription factors for microglia involved in immunosuppression of glioma.

2023-01-08 | GSE185759 | GEO

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