Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis

Vitucci, Mark; Karpinich, Natalie O.; Bash, Ryan; Werneke, Andrea M.; Schmid, Ralf S.; White, Kristen; McNeill, Robert S.; Huff, Byron; Wang, Xin Wei; Dyke, Terry Van; Miller, C. Ryan

doi:10.1093/neuonc/not084

Cited by 62 publications

(110 citation statements)

References 46 publications

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“…Thus, if the induced mutations fail to immortalize cells and protect them from oncogene-induced senescence, they cannot be serially passaged for phenotypic characterization in vitro. Viral oncoproteins such as HPV E6/E7 and SV40 large T antigen have been extensively utilized to immortalize many human and murine cell types in culture, including astrocytes 13,26,30 . We have previously shown that ablation of the G1/S cell cycle checkpoint with T was sufficient to immortalize cortical astrocytes, but not sufficient to cause lethal astrocytomas in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, GEM-derived cortical astrocytes can be used to determine the efficacy of targeted inhibitors in vitro. We have shown previously that treatment with low dose PI-103, a dual mTOR/PI3K inhibitor, inhibited PI3K signaling without affecting cell viability 30 . However, the cytostatic/cytotoxic effects of higher PI-103 doses were not determined.…”

Section: G12dmentioning

confidence: 99%

“…The role of initiating cell type and co-occurring mutations in astrocytoma pathogenesis are difficult to determine using established human GBM cell lines or PDX because they are derived from end-stage tumors that have accumulated extensive genetic mutations in undefined cell types during the course of malignant progression. In contrast, all grades of astrocytomas can be modeled using nGEM by inducing defined genetic mutations within specific purified brain cell types 11,30 . Thus, the influence of specific genetic mutations and cell type on cellular and molecular phenotypes can be determined in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Similar to established human GBM cell lines, initial in vitro drug testing using nGEM can be used to prioritize drugs for in vivo testing utilizing the same cells. Tumorigenesis in vivo can then be determined by allografting nGEM cells orthotopically into the brains of immune-competent syngeneic littermates 30 . These orthotopic allograft models therefore permit in vivo testing not only of conventional cytotoxic and targeted therapies, but immune-modulatory and stroma-targeted therapies as well.…”

Section: Introductionmentioning

confidence: 99%

“…We and others have developed astrocytoma nGEM using primary cells -astrocytes, NSC, or oligodendrocyte precursor cells (OPC) -harvested from GEM [30][31][32][33][34] . The rationale behind the development of an astrocytoma nGEM was to create a model to determine the phenotypic consequences of oncogenic mutations in specific cell types that could potentially be used for preclinical drug testing in vitro and in vivo in immune-competent animals.…”

Section: Introductionmentioning

confidence: 99%

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Modeling Astrocytoma Pathogenesis In Vitro and In Vivo Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice

McNeill¹,

Schmid²,

Bash

et al. 2014

JoVE

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Current astrocytoma models are limited in their ability to define the roles of oncogenic mutations in specific brain cell types during disease pathogenesis and their utility for preclinical drug development. In order to design a better model system for these applications, phenotypically wild-type cortical astrocytes and neural stem cells (NSC) from conditional, genetically engineered mice (GEM) that harbor various combinations of floxed oncogenic alleles were harvested and grown in culture. Genetic recombination was induced in vitro using adenoviral Cre-mediated recombination, resulting in expression of mutated oncogenes and deletion of tumor suppressor genes. The phenotypic consequences of these mutations were defined by measuring proliferation, transformation, and drug response in vitro. Orthotopic allograft models, whereby transformed cells are stereotactically injected into the brains of immune-competent, syngeneic littermates, were developed to define the role of oncogenic mutations and cell type on tumorigenesis in vivo. Unlike most established human glioblastoma cell line xenografts, injection of transformed GEMderived cortical astrocytes into the brains of immune-competent littermates produced astrocytomas, including the most aggressive subtype, glioblastoma, that recapitulated the histopathological hallmarks of human astrocytomas, including diffuse invasion of normal brain parenchyma. Bioluminescence imaging of orthotopic allografts from transformed astrocytes engineered to express luciferase was utilized to monitor in vivo tumor growth over time. Thus, astrocytoma models using astrocytes and NSC harvested from GEM with conditional oncogenic alleles provide an integrated system to study the genetics and cell biology of astrocytoma pathogenesis in vitro and in vivo and may be useful in preclinical drug development for these devastating diseases. Video LinkThe video component of this article can be found at

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Section: Discussionmentioning

confidence: 99%

Section: G12dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Modeling Astrocytoma Pathogenesis In Vitro and In Vivo Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice

McNeill¹,

Schmid²,

Bash

et al. 2014

JoVE

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TRIM24 Cooperates with Ras Mutation to Drive Glioma Progression through snoRNA Recruitment of PHAX and DNA‐PKcs

Xu,

Chen,

et al. 2024

Advanced Science

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The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep‐GBM)‐like tumors. Co‐transfection of TRIM24 with HRasV12 also induces Ep‐GBM‐like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep‐GBM specimens. Using single‐cell RNA‐sequencing (scRNA‐Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku‐dependent DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA‐PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep‐GBM‐like transformation. Targeting DNA‐PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep‐GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep‐GBM‐like transformation and suggest a potential therapeutic strategy for patients with Ep‐GBM.

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Construction of lncRNA‐associated ceRNA networks to identify prognostic lncRNA biomarkers for glioblastoma

Liu

Wang

Yang

et al. 2020

J of Cellular Biochemistry

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Long noncoding RNAs (lncRNAs) serve as competitive endogenous RNAs (ceRNAs) that play significant regulatory roles in the pathogenesis of tumors. However, the role of lncRNAs, especially the lncRNA-related ceRNA regulatory network, in glioblastoma (GBM) has not been fully elucidated. The goal of the current study was to construct lncRNA-microRNA-mRNA-related ceRNA networks for further investigation of their mechanism of action in GBM. We downloaded data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases and identified differential lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) associated with GBM. A ceRNA network was constructed and analyzed to examine the relationship between lncRNAs and patients' overall survival. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGGs) were used to analyze the related mRNAs to indirectly explain the mechanism of action of lncRNAs. The potential effective drugs for the treatment of GBM were identified using the connectivity map (CMap). After integrated analysis, we obtained a total of 210 differentially expressed lncRNAs, 90 differentially expressed miRNAs, and 2508 differentially expressed mRNAs (DEmRNAs) from the TCGA and GEO databases. Using these differential genes, we constructed a lncRNA-associated ceRNA network. Six lncRNAs in the ceRNA network were associated with the overall survival of patients with GBM. Through KEGG analysis, it was found that the DEmRNAs involved in the network are related to cancer-associated pathways, for instance, mitogen-activated protein kinase and Ras signaling pathways. CMap analysis revealed four small-molecule compounds that could be used as drugs for the treatment of GBM. In this study, a multi-database joint analysis was used to construct a lncRNA-related ceRNA network to help identify the regulatory functions of lncRNAs in the pathogenesis of GBM.

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Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis

Cited by 62 publications

References 46 publications

Modeling Astrocytoma Pathogenesis <em>In Vitro</em> and <em>In Vivo</em> Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice

Modeling Astrocytoma Pathogenesis <em>In Vitro</em> and <em>In Vivo</em> Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice

TRIM24 Cooperates with Ras Mutation to Drive Glioma Progression through snoRNA Recruitment of PHAX and DNA‐PKcs

Construction of lncRNA‐associated ceRNA networks to identify prognostic lncRNA biomarkers for glioblastoma

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