The molecular landscape of glioma in patients with Neurofibromatosis 1.
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PROVIDER: EGAS00001003186 | EGA |
REPOSITORIES: EGA
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Project description:Solid cancers develop within a supportive microenvironment that promotes tumor formation and continued growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically-engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), previous studies have demonstrated that microglia are important for glioma formation and maintenance. To identify the tumor-associated microglial factors that support glioma growth (gliomagens), we employed a comprehensive large scale discovery effort using optimized advanced RNA-sequencing methods. Candidate gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative RT-PCR and RNA FISH following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, Ccl5 was identified as a highly expressed chemokine in both genetically engineered Nf1 mouse and human optic gliomas. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, Ccl5 inhibition with neutralizing antibodies reduced Nf1 mouse optic glioma growth in vivo. Collectively, these findings establish Ccl5 as critical stromal growth factor in low-grade glioma maintenance relevant to future microglia-targeted therapies for brain tumors.
2016-08-17 | GSE65831 | GEO
Project description:Pediatric low-grade glioma incidence has been rising in the U.S., mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the U.S. is largely driven by diet, given the abudnance of high fat and high sugar food choices. We identified that combined maternal and postnatal obesogenic (Ob) diet exposure accelerated glioma formation in murine Neurofibromatosis type 1 (Nf1) optic pathway glioma (OPG)-forming mice, a model of pediatric glioma formation. Postnatal dietary exposure alone could not fully recaptiulate these effects, indicating maternal exposure was critical for this phenotype. To determine how Ob exposure affected gene expression in the optic nerve, we isolated Ob-exposed versus CD-exposed optic nerves and performed RNASeq. Enriched pathways included nervous system development, neuronal signaling and appetite regulation.
2025-05-27 | GSE269517 | GEO
Project description:The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance requires productive interactions between non-neoplastic and neoplastic cells, and employed whole tumor RNA-sequencing and mathematical deconvolution strategies to characterize this low-grade glioma ecosystem as an aggregate of cellular and acellular elements. Using this approach, we demonstrate that optic gliomas generated by altering the germline Nf1 gene mutation, the glioma cell of origin, or the presence of co-existing genetic alterations represent molecularly-distinct tumors. However, these optic glioma tumors share a 25-gene core signature, not found in normal optic nerve, that is normalized by microglia inhibition (minocycline), but not conventional (carboplatin) or molecularly-targeted (rapamycin) chemotherapy. Lastly, we identify a genetic signature conferred by Pten reduction and corrected by PI3K inhibition. This signature predicts progression-free survival in patients with either low-grade or high-grade glioma. Collectively, these findings support the concept that gliomas are composite ecological systems whose biology and response to therapy may be best defined by examining the tumor as a whole.
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Project description:Gene expression profiling in 50 glial brain tumors and 4 normal brains using 42,000-feature cDNA microarrays (from total RNA). Tumors: 50 fresh-frozen glioma specimens subjected to standard WHO classification. Specimens included astrocytic [2 juvenile pilocytic astrocytomas, 1 low-grade astrocytic glioma, 1 anaplastic astrocytomas, 31 glioblastomas (of these 2 secondary glioblastomas and 2 gliosarcomas)], oligodendroglial [5 oligodendrogliomas, 3 anaplastic oligodendrogliomas], and 6 anaplastic oligoastrocytomas tumors. One tumor had been classified as glioneuronal neoplasm. Normal brain was purchased from Stratagene. Stratagene Universal Common Reference was used as reference RNA. The results provide insights into molecular mechanisms and pathways associated with gliomagenesis.
2005-10-06 | E-SMDB-3152 | biostudies-arrayexpress
Project description:The study investigates the role of NF1 mutation and neuronal activity on the initiation of optic pathway glioma, a type of low-grade glioma. the RNAseq dataset investigates mRNA expression profile of human pilocytic astrocytomas (WHO grade I)
2021-03-30 | GSE163071 | GEO
Project description:Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Characterization of DNA copy number changes in 54 glial brain tumors using a cDNA microarray-based comparative genomic hybridization method. Tumors: 54 fresh-frozen glioma specimens subjected to standard WHO classification. Specimens included astrocytic [3 juvenile pilocytic astrocytomas, 1 low-grade astrocytic glioma, 3 anaplastic astrocytomas, 31 glioblastomas (of these 3 secondary glioblastomas and 2 gliosarcomas)], oligodendroglial [5 oligodendrogliomas, 3 anaplastic oligodendrogliomas], and 7 anaplastic oligoastrocytomas tumors. One tumor had been classified as glioneuronal neoplasm. Human male and female genomic reference DNA was purchased from Promega (Promega, Madison, WI). The results provide insights into molecular genetic changes associated with gliomagenesis.
2010-06-10 | E-GEOD-1991 | biostudies-arrayexpress
Project description:Glial progenitor cells (GPCs) of the adult human white matter, which express gangliosides recognized by monoclonal antibody A2B5, are a potential source of glial tumors of the brain. We used A2B5-based sorting to extract progenitor-like cells from a range of human glial tumors, that included low-grade glioma, oligodendroglioma, oligo-astrocytomas, anaplastic astrocytoma, and glioblastoma multiforme. The A2B5+ tumor cells proved tumorigenic upon orthotopic xenograft, and the tumors generated reflected the phenotypes of those from which they derived. Expression profiling revealed that A2B5+ tumor progenitors expressed a cohort of genes by which they could be distinguished from A2B5+ GPCs isolated from normal adult white matter. Most of the genes differentially expressed by glioma-derived A2B5+ cells varied as a function of tumor stage; however, a small number were invariably expressed at all stages of gliomagenesis. These glioma progenitor-associated genes included CD24, SIX1 and EYA1, which were up-regulated at all stages of gliomagenesis, and MTUS1 and SPOCK3, which were down-regulated at all stages of tumor progression. qPCR and immunolabeling confirmed the differential expression of these genes in primary gliomas, while pathway analysis permitted their segregation into differentially active signaling pathways. By comparing the expression patterns of glial tumor progenitors to their identically-isolated normal homologues, we have identified a discrete set of oncogenic pathways by which glial tumorigenesis may be both better understood, and more efficiently targeted. Samples originating from patients with matched disease and/or pathology were considered as replicates either on the basis of exact tumor phenotype, tumor grade, or tumor vs. normal tissue samples.
2013-05-16 | E-GEOD-29796 | biostudies-arrayexpress
Project description:Gene expression profiling in 50 glial brain tumors and 4 normal brains using 42,000-feature cDNA microarrays (from total RNA). Tumors: 50 fresh-frozen glioma specimens subjected to standard WHO classification. Specimens included astrocytic [2 juvenile pilocytic astrocytomas, 1 low-grade astrocytic glioma, 1 anaplastic astrocytomas, 31 glioblastomas (of these 2 secondary glioblastomas and 2 gliosarcomas)], oligodendroglial [5 oligodendrogliomas, 3 anaplastic oligodendrogliomas], and 6 anaplastic oligoastrocytomas tumors. One tumor had been classified as glioneuronal neoplasm. Normal brain was purchased from Stratagene. Stratagene Universal Common Reference was used as reference RNA. The results provide insights into molecular mechanisms and pathways associated with gliomagenesis. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. type: Logical Set Keywords: other
2006-01-27 | GSE2223 | GEO
Project description:Changes in the gut microbiome can have profound effects on the nervous system through modulation of T cell and microglia function. Since our prior studies demonstrated that T cells and microglia positively regulate low-grade glioma growth through the establishment of T cell-microglia immune circuit, we sought to explore the impact of changes in the gut microbiota on tumor biology. For these studies, genetically engineered Neurofibromatosis type 1 (NF1) optic glioma (Nf1-OPG) mice were raised in a germ-free environment or treated with antibiotics to deplete gut bacteria. First, we demonstrated that Nf1-OPG mice raised in a germ-free (gnotobiotic) environment or treated with specific antibiotics lacked optic gliomas and had improved OPG-induced retinal pathology (increased retinal nerve fiber layer thickness). Second antibiotic-treated Nf1-OPG mice gavaged with fecal microbiota from Nf1-OPG mice raised in a standard barrier facility restored optic glioma growth. Third, we showed that both germ-free and antibiotic-treated Nf1-OPG mice exhibited reduced intra-tumoral CD8+ T cell content resulting from decreased microglia chemokine production. Collectively, these findings establish a mechanistic relationship between the gut microbiota and brain tumor growth relevant to potential therapeutic interventions for pediatric low-grade gliomas.
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Project description:Mutations in isocitrate dehydrogenase (IDH)-1/2 are defining drivers of low-grade gliomagenesis. However, mutant IDH alone is not sufficient for malignant transformation, and additional events are required for the development of low-grade glioma. While specific genetic lesions have been identified to contribute to low-grade gliomagenesis, less is known about the signaling pathways involved in acquiring malignancy. To identify prerequisites of IDH mutant tumorigenesis, we modulated pathways previously implicated in glioma initiation using a tractable in vitro model system for early IDH1R132H-dependent gliomagenesis. Through the use of chemical compounds, we targeted WNT/GSK3, TGF-β and NOTCH-signaling, assessing their functional, transcriptional, and translational impacts. Expression of LGG-related marker L1CAM was affected by perturbation of all pathways, though only modulation of WNT/GSK3-signaling resulted in profound molecular transformation, including glioma-associated genes and programs regulating cellular architecture and cell replication. This was accompanied by altered cell morphology, migration capacity, and enhanced proliferation. Transcription factor RUNX2 was identified as a potential downstream effector, whose inhibition abrogated cell proliferation. Disrupted WNT/GSK3 signaling in a model system of early low-grade gliomagenesis fundamentally impacted cell fate, as demonstrated by a reshaped transcriptional landscape, aberrant transcription factor activity, ECM restructuring, and altered proliferation capacity. Our data suggests that GSK3 may play a central role during low-grade gliomagenesis, warranting further investigation.
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