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Gene fusion discovery through RNA sequencing of nine human glioblastoma stem cell lines

ABSTRACT:

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.

OTHER RELATED OMICS DATASETS IN: E-GEOD-4536

ORGANISM(S): Homo sapiens

PROVIDER: phs000505.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines.

Lee Jeongwu J Kotliarova Svetlana S Kotliarov Yuri Y Li Aiguo A Su Qin Q Donin Nicholas M NM Pastorino Sandra S Purow Benjamin W BW Christopher Neil N Zhang Wei W Park John K JK Fine Howard A HA

Cancer cell 20060501 5

The concept of tumor stem cells (TSCs) provides a new paradigm for understanding tumor biology, although it remains unclear whether TSCs will prove to be a more robust model than traditional cancer cell lines. We demonstrate marked phenotypic and genotypic differences between primary human tumor-derived TSCs and their matched glioma cell lines. Unlike the matched, traditionally grown tumor cell lines, TSCs derived directly from primary glioblastomas harbor extensive similarities to normal neural ...[more]

PMID: 16697959

Publication: 1/2

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RNA sequencing of human glioma stem cells

Project description: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.

| phs000505 | dbGaP

ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1.

Project description:Glioma is the most common adult primary brain tumor. Its most malignant form, glioblastoma multiforme (GBM), is almost invariably fatal, due in part to the intrinsic resistance of GBM to radiation- and chemotherapy-induced apoptosis. We analyzed B-cell leukemia-2 (Bcl-2) anti-apoptotic proteins in GBM and found myeloid cell leukemia-1 (Mcl-1) to be the highest expressed in the majority of malignant gliomas. Mcl-1 was functionally important, as neutralization of Mcl-1 induced apoptosis and increased chemotherapy-induced apoptosis. To determine how Mcl-1 was regulated in glioma, we analyzed the promoter and identified a novel functional single nucleotide polymorphism in an uncharacterized E26 transformation-specific (ETS) binding site. We identified the ETS transcription factor ELK4 as a critical regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 and increase sensitivity to apoptosis. Importantly the presence of the single nucleotide polymorphism, which ablated ELK4 binding in gliomas, was associated with lower Mcl-1 levels and a greater dependence on Bcl-xL. Furthermore, in vivo, ELK4 downregulation reduced tumor formation in glioblastoma xenograft models. The critical role of ELK4 in Mcl-1 expression and protection from apoptosis in glioma defines ELK4 as a novel potential therapeutic target for GBM.

2011-01-01 | S-EPMC3199151 | BioStudies

Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway.

Project description:Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer. The way in which glioma cells interact with their microenvironment and acquire the phenotypes of CSCs remains elusive. We investigated how communication between vascular endothelial cells and glioma cells promoted the properties of glioma stem cells (GSCs). We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM). In both in vitro and in vivo studies, we found that endothelial cells promoted the appearance of CSC-like glioma cells, as demonstrated by increases in tumourigenicity and expression of stemness genes such as Sox2, Olig2, Bmi1 and CD133 in glioma cells that were co-cultured with endothelial cells. Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo. Endothelial cells with Shh knockdown failed to promote Hedgehog (HH) pathway activation and CSC-like phenotype formation in co-cultured glioma cells. By examination of glioma tissue specimens from 65 patients, we found that the survival of glioma patients was closely correlated with the expression of both Shh by endothelial cells and Gli1 by perivascular glioma cells. Taken together, our study demonstrates that endothelial cells in the tumour microenvironment provide Shh to activate the HH signalling pathway in glioma cells, thereby promoting GSC properties and glioma propagation.

1000-01-01 | S-EPMC4260128 | BioStudies

Icariside II induces cell cycle arrest and apoptosis in human glioblastoma cells through suppressing Akt activation and potentiating FOXO3a activity.

Project description:Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and currently chemotherapeutic options for GBM are very limited. Given the poor prognosis, the development of novel anti-GBM agents is quite urgent. Using two human glioma cells (U87 and A172 cells), we demonstrated that Icariside II (ICA II), an active flavonoid compound derived from Epimedium koreanum, could inhibit GBM cell growth in a dose dependent manner. Wound healing data suggested that ICA II also inhibited the migration of human glioma cells. Mechanistically, ICA II induced apoptosis and cell cycle arrest, and this cytotoxic effect was dependent on the reduction of Forkhead box O3a(FOXO3a) phosphorylation mediated by Akt and the enrichment of nuclear FOXO3a, which initiated the transcription of p21/p27. Importantly, the cytotoxic effect induced by ICA II could be reversed by silencing the expression of FOXO3a, suggesting the critical role of FOXO3a in this process. Taken together, we propose ICA II as a potential novel anti-GBM candidate with a mechanism of inhibiting cell proliferation and inducing apoptosis through suppressing Akt activation and potentiating FOXO3a activity.

1000-01-01 | S-EPMC5446533 | BioStudies

Radiation-induced PGE2 sustains human glioma cells growth and survival through EGF signaling.

Project description:Glioblastoma Multiforme (GBM) is the most common brain cancer in adults. Radiotherapy (RT) is the most effective post-operative treatment for the patients even though GBM is one of the most radio-resistant tumors. Dead or dying cells within the tumor are thought to promote resistance to treatment through mechanisms that are very poorly understood. We have evaluated the role of Prostaglandin E2 (PGE2), a versatile bioactive lipid, in GBM radio-resistance. We used an in vitro approach using 3D primary cultures derived from representative GBM patients. We show that irradiated glioma cells produced and released PGE2 in important quantities independently of the induction of cell death. We demonstrate that the addition of PGE2 enhances cell survival and proliferation though its ability to trans-activate the Epithelial Growth Factor receptor (EGFR) and to activate ?-catenin. Indeed, PGE2 can substitute for EGF to promote primary cultures survival and growth in vitro and the effect is likely to occur though the Prostaglandin E2 receptor EP2.

1000-01-01 | S-EPMC4466653 | BioStudies

The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network.

Project description:Glioblastoma multiforme (GBM) is the most common form of primary brain tumor in adults, often characterized by poor survival. Glioma-initiating cells (GiCs) are defined by their extensive self-renewal, differentiation, and tumor initiation properties. GiCs are known to be involved in tumor growth and recurrence, and in resistance to conventional treatments. One strategy to efficiently target GiCs in GBM consists in suppressing their stemness and consequently their tumorigenic properties. In this study, we show that the miR-302-367 cluster is strongly induced during serum-mediated stemness suppression. Stable miR-302-367 cluster expression is sufficient to suppress the stemness signature, self-renewal, and cell infiltration within a host brain tissue, through inhibition of the CXCR4 pathway. Furthermore, inhibition of CXCR4 leads to the disruption of the sonic hedgehog (SHH)-GLI-NANOG network, which is involved in self-renewal and expression of the embryonic stem cell-like signature. In conclusion, we demonstrated that the miR-302-367 cluster is able to efficiently trigger a cascade of inhibitory events leading to the disruption of GiCs stem-like and tumorigenic properties.

2012-01-01 | S-EPMC3263498 | BioStudies

Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a/Bad/Bax axis.

Project description:Glioblastoma multiforme (GBM) is one of the most hypoxic tumors of the central nervous system. Although temozolomide (TMZ) is an effective clinical agent in the GBM therapy, the hypoxic microenvironment remains a major barrier in glioma chemotherapy resistance, and the underlying mechanisms are poorly understood. Here, we find hypoxia can induce the protective response to mitochondrion via HIF-1?-mediated miR-26a upregulation which is associated with TMZ resistance in vitro and in vivo. Further, we demonstrated that HIF-1?/miR-26a axis strengthened the acquisition of TMZ resistance through prevention of Bax and Bad in mitochondria dysfunction in GBM. In addition, miR-26a expression levels negatively correlate with Bax, Bad levels, and GBM progression; but highly correlate with HIF-1? levels in clinical cancer tissues. These findings provide a new link in the mechanistic understanding of TMZ resistance under glioma hypoxia microenvironment, and consequently HIF-1?/miR-26a/Bax/Bad signaling pathway as a promising adjuvant therapy for GBM with TMZ.

1000-01-01 | S-EPMC6233226 | BioStudies

Role of glycosyltransferase PomGnT1 in glioblastoma progression.

Project description:Glioblastoma multiforme (GBM) is the most aggressive and invasive brain tumor, for which novel prognostic markers and predictors of therapeutic response are urgently needed. We reported previously that levels of peptide-O-linked mannose ?-1,2-N-acetylglucosaminyltransferase 1 (PomGnT1) in glioma specimens correlated with tumor grade. However, the prognostic significance of PomGnT1 in glioma patients and its function in GBM progression remain unknown.Clinical relevance of PomGnT1 in GBM patients' prognosis was analyzed both in a clinically annotated expression dataset of 446 GBM tumor specimens and in 82 GBM tumor samples collected at our institution. The function of PomGnT1 in glioma growth and invasion, and the underlying mechanisms of PomGnT1 regulation were explored in vitro and in vivo.PomGnT1 expression in GBM tissues was closely associated with poor prognosis in GBM patients. Forced overexpression of PomGnT1 in glioblastoma cells impaired cell adhesion and increased their proliferation and invasion in vitro. Subsequent in vivo experiments showed that overexpression of PomGnT1 promoted tumor growth and shortened the survival time of tumor-bearing mice in an orthotopic model. Conversely, stable short hairpin RNA-mediated knockdown of PomGnT1 expression produced opposite effects both in vitro and in vivo. Mechanistic studies revealed that activation of epidermal growth factor receptor (EGFR) resulted in EGFR/extracellular signal-regulated kinase-dependent upregulation of PomGnT1, downregulation of receptor-type protein tyrosine phosphatase ?, and activation of ?-catenin pathway signaling.These findings suggest that PomGnT1 promotes GBM progression via activation of ?-catenin and may serve as a prognostic factor for glioma patient survival as well as a novel molecular target for anticancer therapy in malignant glioma.

1000-01-01 | S-EPMC4288519 | BioStudies

Identification of Novel Transcriptome Signature as a Potential Prognostic Biomarker for Anti-Angiogenic Therapy in Glioblastoma Multiforme.

Project description:Glioblastoma multiforme (GBM) is the most common and devastating type of primary brain tumor, with a median survival time of only 15 months. Having a clinically applicable genetic biomarker would lead to a paradigm shift in precise diagnosis, personalized therapeutic decisions, and prognostic prediction for GBM. Radiogenomic profiling connecting radiological imaging features with molecular alterations will offer a noninvasive method for genomic studies of GBM. To this end, we analyzed over 3800 glioma and GBM cases across four independent datasets. The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases were employed for RNA-Seq analysis, whereas the Ivy Glioblastoma Atlas Project (Ivy-GAP) and The Cancer Imaging Archive (TCIA) provided clinicopathological data. The Clinical Proteomic Tumor Analysis Consortium Glioblastoma Multiforme (CPTAC-GBM) was used for proteomic analysis. We identified a simple three-gene transcriptome signature-SOCS3, VEGFA, and TEK-that can connect GBM's overall prognosis with genes' expression and simultaneously correlate radiographical features of perfusion imaging with SOCS3 expression levels. More importantly, the rampant development of neovascularization in GBM offers a promising target for therapeutic intervention. However, treatment with bevacizumab failed to improve overall survival. We identified SOCS3 expression levels as a potential selection marker for patients who may benefit from early initiation of angiogenesis inhibitors.

2020-01-01 | S-EPMC7564118 | BioStudies

Examination of sulfonamide-based inhibitors of MMP3 using the conditioned media of invasive glioma cells.

Project description:Glioblastoma multiforme (GBM) is the deadliest and the most common primary malignant brain tumour. The median survival for patients with GBM is around one year due to the nature of glioma cells to diffusely invade that make the complete surgical resection of tumours difficult. Based upon the connexin43 (Cx43) model of glioma migration we have developed a computational framework to evaluate MMP inhibition in materials relevant to GBM. Using the ilomastat Leu-Trp backbone, we have synthesised novel sulphonamides and monitored the performance of these compounds in conditioned media expressing MMP3. From the results discussed herein we demonstrate the performance of sulfonamide based MMPIs included AP-3, AP-6, and AP-7.

2020-01-01 | S-EPMC7144313 | BioStudies

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