Expression data of three sets of cells: (1) Schwann cells and macrophages from 1m-old WT DRG, (2) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 1m-old neurofibroma, (3) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 7m-old neurofibroma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE78901 | GEO | 2017/05/01
SECONDARY ACCESSION(S): PRJNA314331
REPOSITORIES: GEO
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Project description:Schwann cells and macrophages were dissociated from normal DRGs and 1- and 7-month-old neurofibroma. Schwann cells from neurofibroma have Nf1-/- phenotypes. All macrophages have Nf1+/+ phenotypes. We used microarrays (Affymetrix MoGene 2.0 ST GeneChip) to detect transcriptomal changes between 7-month-old neurofibroma Schwann cells (or macrophages) versus 1-month-old wild-type (or neurofibroma) Schwann cells (or macrophages). Expression data of three sets of cells: (1)Schwann cells and macrophages from 1-month-old wild-type mouse dorsal root ganglia, (2) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 1-month-old neurofibroma, (3) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 7-month-old neurofibroma We chopped mouse DRG/neurofibromas into 1-3 mm^3 pieces and plated them in dissociation medium containing 20mL L-15 (Mediatech), 0.5 mg/mL collagenase type 1 (Worthington; Lakewood, NJ), and 2.5 mg/mL dispase protease type II (Cambrex; East Rutherford, NJ) at 37°C for 4-6 hours with shaking. The dissociation reaction was stopped by adding DMEM +10%FBS. Undigested DRG/tumors were excluded by 100µM cell strainer. Cells were collected by centrifugation. For each microarrays (Schwann cell, macrophage), Affymetrix GeneChip Command Console (v4.0.0) was used to create .chp files. All the probe sets on Affymetrix Mouse Gene 2.0 ST array (Mogene-2_0-st-v1.na33.2.mm10) were summarized by Affymetix Expression Console program using robust multi-chip average (RMA) method . After preprocessing steps, data from two batches were combined and their batch effects were corrected using ComBat method Please note that [1] all MP samples are Nf1+/+ (no mutation on Nf1 gene) and the only difference is their ages (1month, 7month) and [2] the 'nf1' in sample title reperesents "neurofibroma type1 disease", not "Nf1 gene".
2017-05-01 | E-GEOD-78901 | biostudies-arrayexpress
Project description:Analysis of the effect of NF1 second hit mutation to the reading of the whole human genome by comparing the gene expression profiles of neurofibroma derived Schwann cell cultures representing two different NF1 genotypes (NF1+/- and NF1-/-).
2016-12-22 | GSE32029 | GEO
Project description:To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome in which affected individuals develop plexiform neurofibroma (PN). These benign tumors are driven by NF1 loss in Schwann cells (SC). By comparing normal nerve cells to PN cells using single cell and bulk RNA sequencing, we identified changes in five SC populations, including a de novo Schwann cell progenitor-like population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and CD74, and showed dramatic expansion of immune and stromal cell populations; in human PN, immune and stromal cells comprised 90% of cells. Label transfer enabled verification of each SC population and predicted tumor unique patterns of cell-cell communication in each SC population. We identified PROS-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NFkB as deregulated in NF1 SC populations, including SCP-like cells. Each receptor-ligand pair was predicted to influence surrounding cells in mouse and human. These findings highlight remarkable changes in all PN cells driven by loss of NF1 in multiple types of SCs and identify therapeutic targets for PN.
2022-11-23 | GSE181985 | GEO
Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the Cxcl10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.
2018-11-28 | GSE122999 | GEO
Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor, Cxcr3, prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.
2019-02-24 | GSE122730 | GEO
Project description:Patients with neurofibromatosis type 1 (NF1) develop benign plexiform neurofibromas that frequently progress to become malignant peripheral nerve sheath tumors (MPNSTs). A genetically engineered mouse model that accurately models plexiform neurofibroma-MPNST progression would facilitate the identification of somatic mutations driving this process. We have previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P0-GGF?3 mice) develop MPNSTs. To determine whether P0-GGF?3 mice accurately model neurofibroma-MPNST progression, cohorts of these animals were followed to death and necropsied. 94% of the mice developed multiple neurofibromas, with 70% carrying smaller numbers of MPNSTs; nascent MPNSTs were identified within neurofibromas, suggesting that these sarcomas arise from neurofibromas. Although neurofibromin expression was maintained, P0-GGF?3 MPNSTs, like human NF1-associated MPNSTs, demonstrated Ras hyperactivation. P0-GGF?3 MPNSTs also showed abnormalities in the p16INK4A-cyclin D/CDK4-Rb and p19ARF-Mdm-p53 pathways analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P0-GGF?3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 genes previously implicated in neoplasia (e.g., Pten, Tpd52, Myc , Gli1, Xiap, Bbc3/PUMA). Array CGH also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P0-GGF?3 mice represent a robust model of neurofibroma-MPNST progression that can be used to identify novel genes driving neurofibroma and MPNST pathogenesis. Array CGH comparison of malignant peripheral nerve sheath tumor (MPNST) cells vs non-neoplastic Schwann cells
2012-12-31 | E-GEOD-40212 | biostudies-arrayexpress
Project description:Neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder, affecting 1 in 3,500 individuals worldwide and predisposing to cancer. Germline mutations in the NF1 gene, encoding the p21Ras GTPase-activating protein (GAP) neurofibromin, are the underlying cause for NF1. Somatic inactivation of the wild type copy of NF1 leads to deregulated Ras signaling. Clinical manifestations are diverse for NF1 patients, but the predominant lesions are plexiform neurofibroma (PNF), arising from the Schwann cell (SC) lineage. While PNF are generally benign, approximately 10% of patients will experience PN progression to highly aggressive malignant peripheral nerve sheath tumors (MPNST) with poor prognosis. There are currently no approved targeted therapies for PNF or MPNST. In this study, we used a conditional mouse model of NF1, test the multi-receptor tyrosine kinase inhibitor, cabozantinib (XL184). Mice were treated with vehicle or with cabozantinib for 3 or 7 days. Tissue was harvested, lysates prepared, and the lysate was used for kinome profiling. From cell lines or tumor tissue, protein lysates are prepared and passed over an affinity matrix consisting of Sepharose beads covalently coupled to a mixture of linker-adapted Type I kinase inhibitors. Kinase capture is reproducible and is a function of affinity for kinases for the immobilized inhibitors, expression level of the kinase, as well as the activation state of the kinase. Following affinity purification, kinases are identified and their multiplexed kinase inhibitor bead binding quantified by mass spectrometry (MIB/MS). Our goal is to identify the kinome changes in NF1 plexiform neurofibroma induced by cabozantinib treatment.
2020-11-19 | PXD019138 | Pride
Project description:Neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder, affecting 1 in 3,500 individuals worldwide and predisposing to cancer. Germline mutations in the NF1 gene, encoding the p21Ras GTPase-activating protein (GAP) neurofibromin, are the underlying cause for NF1. Somatic inactivation of the wild type copy of NF1 leads to deregulated Ras signaling. Clinical manifestations are diverse for NF1 patients, but the predominant lesions are plexiform neurofibroma (PNF), arising from the Schwann cell (SC) lineage. While PNF are generally benign, approximately 10% of patients will experience PN progression to highly aggressive malignant peripheral nerve sheath tumors (MPNST) with poor prognosis. There are currently no approved targeted therapies for PNF or MPNST. In this study, we used a conditional mouse model of NF1, test the multi-receptor tyrosine kinase inhibitor, cabozantinib (XL184). Mice were treated with vehicle or with cabozantinib for 3 or 7 days. Tissue was harvested, lysates prepared, and the lysate was used for kinome profiling. From cell lines or tumor tissue, protein lysates are prepared and passed over an affinity matrix consisting of Sepharose beads covalently coupled to a mixture of linker-adapted Type I kinase inhibitors. Kinase capture is reproducible and is a function of affinity for kinases for the immobilized inhibitors, expression level of the kinase, as well as the activation state of the kinase. Following affinity purification, kinases are identified and their multiplexed kinase inhibitor bead binding quantified by mass spectrometry (MIB/MS). Our goal is to identify the kinome changes in NF1 plexiform neurofibroma induced by cabozantinib treatment.
2023-05-18 | PXD019005 | Pride
Project description:To identify possible novel targets for the treatment of plexiform neurofibroma formation through a synthetic lethal shRNA library screen in the tumorigenic cell of origin, Schwann cells.
2019-11-30 | E-MTAB-8398 | biostudies-arrayexpress
Project description:Understanding biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumors is essential, as tumor biomarkers, prognostic factors and therapeutics are all lacking. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (n = 22), malignant peripheral nerve sheath tumor (MPNST) cell lines (n = 13), benign neurofibromas (n = 26) and MPNST (n = 6). Dermal and plexiform neurofibromas were indistinguishable. A prominent theme in the analysis was aberrant differentiation. Neurofibromas repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes upregulated in the sarcomas were significantly enriched for genes activated in neural crest cells. We validated differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in neurofibroma and MPSNT tissue sections and targeting SOX9 - strongly expressed in NF1-related tumors - caused MPNST cell death. SOX9 is a biomarker of neurofibroma and MPNST, and possibly a therapeutic target in NF1. Keywords: tumor stage 86 microarrays, consisting of 77 samples and 9 batch reference samples: NHSC (10), dNFSC (11), pNFSC (11), MPNST cell lines (13), dNF (13), pNF (13), MPNST (6)
2009-07-15 | E-GEOD-14038 | biostudies-arrayexpress