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Characterization of the human HSC1L cell line with knockout of NF1

ABSTRACT: An RNA-seq study of altered gene expression in serum starved human HSC1L cells (an immortalized Schwann cell line) with and without knockout (KO) of NF1. The analysis of the RNA-seq data led to the identification of a set of genes disregulated in the NF1 KO samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100181 | GEO | 2025/03/24

REPOSITORIES: GEO

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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

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 37Â°C for 4-6 hours with shaking. The dissociation reaction was stopped by adding DMEM +10%FBS. Undigested DRG/tumors were excluded by 100ÂµM 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

Global proteomics and affinity mass spectrometry analysis of human Schwann cells indicates that loss of NF1 alters cellular and mitochondrial metabolism - Global

Project description:Detailed global proteomics analysis for NF1 deficient cells and tissues is lacking. We investigated proteomes from immortalized human Schwann cells with (+/+) and without (-/-) NF1 to evaluate potential biomarkers and targets in NF1 deficient cells. We identified over 1900 proteins in both cell lines and find 148 proteins with differential expression levels based on genotype. Following Ingenuity Pathway analysis (IPA), we found multiple pathways were altered including decrease in “oxidative phosphorylation,” increases in “mitochondrial dysfunction”, and “glycolysis”, as well as changes in “Myelination Signaling Pathway.” Next, we stably transfected NF1 -/- cells with tagged mNf1 cDNAs (either WT or variant) and again evaluated the global proteome. We identified an overall trend of metabolic differences pertaining to oxidative phosphorylation, mitochondria dysfunction, and glycolysis in the mutant cDNA expressing cells compared to WT cDNA cells. We then validated differential expression of the following proteins: LAMC1, CYB5R3, and SOD2. Additionally, we used the encoded Strep tag on the cDNA to affinity purity NF1 Protein-Protein interactors from the Schwann cells expressing WT and variant cDNAs. We were able to identify 98 PPIs and 9 overlap with prior HEK293 cell datasets while 89 are unique to Schwann cells. GO analysis indicates many of these PPIs play a role in protein-transporting ATP synthase complex or are involved with intermediate filaments. While we were able to show that some of these bind differentially to variant isoforms, variations within NF1 did not significantly impact ability to bind partners. Finally, we show that loss of NF1 impacts Schwann cell mitochondrial respiration via Seahorse validating our proteomics data and indicating that NF1 plays a significant role in in mitochondrial metabolism that results in proteomics changes in Schwann cells.

2025-05-07 | PXD052439 | Pride

Global proteomics and affinity mass spectrometry analysis of human Schwann cells indicates that loss of NF1 alters cellular and mitochondrial metabolism - PPI SC study

2025-05-07 | PXD052442 | Pride

Genome-wide gene expression analysis of neurofibroma-derived NF1+/- and NF1-/- Schwann cells

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

2017-05-01 | GSE78901 | GEO

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumor

Project description:Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1 proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1 deficient cells, which identified 23 compounds capable of killing NF1 deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All trugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform has yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

2024-03-21 | GSE262030 | GEO

NF1 microdeletions characterization by custom high-resolution array CGH

Project description:To allow accute charaterization of NF1 locus constitutional microdeletion in 70 NF1 patients, a custom array CGH was developped. Goal was to obtain genomic rearrangements fine characterization in order to perform genotype-phenotype correlation in NF1 microdeleted patients. To serve as a reference group in our genotype-phenotype correlation study in NF1 microdeletion patients, non-deleted NF1 patients (i.e. patients with an intragenic NF1 mutation) were also selected from our database. A total of 389 NF1 patients were included in the reference group of non-deleted patients. Multiple logistic regression was performed to test the association of each clinical feature individually with the type of constitutional NF1 mutation (intragenic mutation vs. microdeletion). The phenotypic traits of the 389 reference patients are available in the "GSE19730_control_patient_characteristics.txt" supplementary file on the Series record. NF1 locus microdeletions characterization vs reference sample (pool of six normal control DNAs)

2010-05-26 | E-GEOD-19730 | biostudies-arrayexpress

Transcriptome profiling tumor cells-of-origin from Nf1 and Nf1-Arf null murine model of Neurofibromatosis Type 1

Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Transformation from Nf1-null benign plexiform neurofibromas is driven by the loss of the Cdkn2a (Arf) locus. Here, genetically engineered mouse models with floxed Nf1 and combined Nf1 and Arf alleles were used. Schwann cell precursor cells (the tumor cell-of-origin) were isolated from the nerve root (dorsal root ganglia) of embryos at day 13.5. These cells, termed DRG/nerve root neurosphere cells (DNSCs) were established, and either control adenoviral infection (GFP) was performed, or adenoviral Cre-GFP infection used to conditionally ablate Nf1 or Nf1-Arf. mRNA sequencing was performed using Nf1 (control, GFP infected or “GFP”), Nf1 (Cre-GFP infected or “CRE”), or Nf1-Arf (Cre-GFP infected or “ARF”) to evaluate the effects on the transcriptome.

2024-12-30 | GSE232451 | GEO

Cellular origin, tumour progression and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells

Project description:Patients carrying an inactive NF1 allele develop tumours of Schwann cell origin called neurofibromas (NFs). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNFs). However, this has not been the case for cutaneous neurofibromas (cNFs), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs, and provides insights on disease mechanisms, revealing a long, multistep pathological process in which inflammation play pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas.

2020-03-10 | GSE117781 | GEO

Transcription profiling of rat Schwann cells in response to NF1 RNAi treatment and the MEK inhibitor U0126

Project description:Comparison of the changes in the gene expression profile of cells in which NF1 has been knocked down by RNAi in the presence/absence of the MEK inhibitor UO126 Experiment Overall Design: Primary Rat Schwann cells were transiently transfected with either scrambled (control) or NF1 RNAi oligonucleotides in the presence/absence of the MEK inhibitor UO126. Total RNA was then harvested 48 hours post-transfection. Three independent biological replicates were analysed.

2008-04-07 | E-GEOD-10376 | biostudies-arrayexpress

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