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

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Luke Adam Noon

PROVIDER: E-GEOD-10376 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression profiling of mammalian 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 Keywords: RNAi knock-down of NF1 gene

2008-02-08 | GSE10376 | GEO

Intrinsic Resistance to MEK Inhibition Through BET Protein Mediated Kinome

Project description:Mutation or deletion of Neurofibromin (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF-MEK-ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of RTKs and their downstream RAF and PI3K signaling overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of BET proteins using BET bromodomain inhibitors (BETi) blocked MEKi-induced RTK reprogramming, indicating BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC.

2019-05-17 | GSE127886 | GEO

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

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

Selumetinib in adults with NF1 and inoperable plexiform neurofibroma

Project description:The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, an open-label phase 2 study of selumetinib in adults with NF1 PNs was conducted. Correlative analysis included extraction of RNA followed by sequencing. Samples include paired specimens collected before and on treatment.

2024-10-07 | GSE277520 | GEO

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors, despite transcriptional feedback onto ERK.

Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.

2012-12-28 | GSE41747 | GEO

Transcription profiling of mouse chondrocytes treated with MEK/ERK pathway inhibitors

Project description:Objectives: To identify similarities and differences in gene expression data in the MEK/ERK and PI3K pathways and to determine how histone modification affects these same pathways. Goal: To identify and functionally characterize novel targets of these signaling pathways in the context of chondrocyte differentiation. Experiment Overall Design: Cartilage derived from the hind limbs of CD1 mice staged at 15.5 days of embryonic development were dissected and plated in primary chondrocyte monolayer cultures. Cells were treated with MEK/ERK pathway inhibitors (SB202190 and UO126), a PI3K inhibitor (LY294002), a histone deacetylase inhibitor (Trichostatin A) and the vehicle control (DMSO) for 24 hours. Total RNA was isolated from these samples and hybridized to Affymetrix MOE 430 2.0 chips at the London Regional Genomics facility. Experiment Overall Design: A total of 15 genechips were analyzed between 4 treatments and the vehicle (DMSO) control. Three biological replicates per treatment were executed. Experiment Overall Design: Experiment Overall Design:

2009-05-11 | E-GEOD-15069 | biostudies-arrayexpress

Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers

Project description:The NF1 tumor suppressor encodes a RAS GTPase-Activating Protein (RasGAP). Accordingly, deregulated RAS signaling underlies the pathogenesis of NF1-mutant cancers. However, while various RAS effector pathways have been shown to function in these tumors, it is currently unclear which specific proteins within these broad signaling pathways represent optimal therapeutic targets. Here we identify mTORC1 as the key PI3K pathway component in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. We also report that combined mTORC1/MEK inhibition is required to promote tumor regression in animal models, but only when the inhibition of both pathways is sustained. Transcriptional profiling studies were also used to establish a predictive signature of effective mTORC1/MEK inhibition in vivo. Within this signature, we unexpectedly found that the glucose transporter gene, GLUT1, was potently suppressed but only when both pathways were effectively inhibited. Moreover, unlike VHL and LKB1 mutant cancers, reduction of 18F-FDG uptake measured by FDG-PET required the effective suppression of both mTORC1 and MEK. Together these studies identify optimal and sub-optimal therapeutic targets in NF1-mutant malignancies and define a non-invasive means of measuring combined mTORC1/MEK inhibition in vivo, which can be readily incorporated into clinical trials. 8 samples, in duplicate, 2X vehicle, 2X Rapamycin, 2X PD-0325901, 2X Rapamycin/PD-0325901

2014-07-01 | E-GEOD-57141 | biostudies-arrayexpress

Transcription profiling of mouse chondrocytes obtained from CD1 mice were retead with MEK/ERK pathway inhibitors

Project description:Objectives: To identify similarities and differences in gene expression data in the MEK/ERK and PI3K pathways and to determine how histone modification affects these same pathways. Goal: To identify and functionally characterize novel targets of these signaling pathways in the context of chondrocyte differentiation. Experiment Overall Design: Cartilage derived from the hind limbs of CD1 mice staged at 15.5 days of embryonic development were dissected and plated in primary chondrocyte monolayer cultures. Cells were treated with MEK/ERK pathway inhibitors (SB202190 and UO126), a PI3K inhibitor (LY294002), a histone deacetylase inhibitor (Trichostatin A) and the vehicle control (DMSO) for two hours. Total RNA was isolated from these samples and hybridized to Affymetrix MOE 430 2.0 chips at the London Regional Genomics facility. Experiment Overall Design: A total of 15 genechips were analyzed between 4 treatments and the vehicle (DMSO) control. Three biological replicates per treatment were executed.

2008-06-16 | E-GEOD-8488 | biostudies-arrayexpress

2017-05-01 | GSE78901 | GEO

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