Gene profiles of pathway interference downstream neurofibromin signaling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE39764 | GEO | 2013/03/15
SECONDARY ACCESSION(S): PRJNA171610
REPOSITORIES: GEO
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Project description:Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of mutations in the neurofibromatosis type I gene (Nf1) as well as sporadically. Plexiform neurofibromas in NF1 patients have a significant risk of developing into MPNSTs leading to increased morbidity and mortality from this syndrome. Surgery is the primary intervention but it is not always effective due to the tendency of MPNSTs to infiltrate the surrounding tissue or grow in an inoperable location. Neurofibromin, the protein coded by the Nf1 gene, functions as a GTPase activating protein (GAP) whose mutation leads to constitutive activation of RAS and mitogen-activated protein kinase (MAPK) signaling in NF1 patients’ tumors. However, therapeutic targeting of RAS and MAPK have had limited success (Kalamarides, et al., 2012). In this study, we modulated NRAS, MEK1/2 and neurofibromin levels in MPNST cell lines and determined the global gene expression changes that were associated with each experimental condition. Furthermore, gene expression changes due to neurofibromin deficiency but independent of NRAS and MEK1/2 regulation were characterized for the first time in MPNST cell lines. There are total 4 comparison scenarios. Each scenario has two different samples to compare and each sample has three replicates. Comparison 1: ST88-14 cell line versus normal human schwann cell; comparison 2: U0126 treated ST88-14 versus DMSO treat ST88-14 as control; comparison 3: siNRAS treated ST88-14 versus scrambled control treated ST88-14 cell line; comparison 4: siNf1 treated STS26T cell line versus scrambled control RNA treated STS26T cell line.
2013-03-15 | E-GEOD-39764 | biostudies-arrayexpress
Project description:Neurofibromin (NF1) is a fundamental inhibitor of cell growth that is conserved from yeast to humans. NF1 negatively regulates oncogenic RAS proteins by accelerating the hydrolysis of RAS-bound GTP. This activity blocks growth factor signalling upstream of both mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. However, the structure and regulatory mechanisms of NF1 have remained elusive. Here we report crosslinking mass spectrometry analysis of the 320 kDa NF1 protein.
2022-08-12 | PXD023593 | Pride
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: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-GGFβ3 mice) develop MPNSTs. To determine whether P0-GGFβ3 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-GGFβ3 MPNSTs, like human NF1-associated MPNSTs, demonstrated Ras hyperactivation. P0-GGFβ3 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-GGFβ3 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-GGFβ3 mice represent a robust model of neurofibroma-MPNST progression that can be used to identify novel genes driving neurofibroma and MPNST pathogenesis.
2012-12-31 | GSE40212 | GEO
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays.
2011-05-18 | GSE29343 | GEO
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays. We analyzed triceps muscles from 4 three-month-old wt controls and 4 three-month-old Nf1Prx1 mice using the Affymetrix Mouse Gene 1.0 ST platform. Array data was processed by the Affymetrix Exon Array Computational Tool. RNA isolated from each animal was hybridized to a separate microarray.
2011-05-18 | E-GEOD-29343 | biostudies-arrayexpress
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within pre-existing benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation and respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST tumor models indicates that MEK inhibition has poor anti-tumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors was performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with hydroxychloroquine as a novel treatment approach for NF1 MPNSTs.
2024-12-12 | GSE283902 | GEO
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
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. 83 microarrays: Mouse control (15), Mouse neurofibroma (15), Mouse MPNST (18); Human nerve (3), Human neurofibroma (26), Human MPNST (6) We used the same human tumor samples as in series GSE14038 (dNF, pNF and MPNST). However, instead of referencing gene expression changes to the normal human Schwann cell samples (NHSC) as we did in series GSE14038, we generated three (new) normal nerve samples (samples jan-N1-3) and referenced gene expression changes to those samples. Moreover, the analysis of series GSE14038 evaluated changes in expression between NHSC, benign tumor subtypes (dNF and pNF), and malignant tumors (MPNST), while our present submission evaluated changes between normal nerve, benign tumors (combined dNF and pNF),and malignant tumors (MPNST). The Series supplementary 'merged_data.txt' file contains the data for 9,891 transcripts that were statistically different in at least one of the two species and present in both mouse and human data sets.
2012-12-28 | E-GEOD-41747 | biostudies-arrayexpress
Project description:Background: Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. Methods: We generated five patient-derived MPNST orthoxenograft models (three NF1-related and two sporadic) and performed an exhaustive histological and molecular characterization of primary MPNSTs and their corresponding orthoxenografts. Finally, orthoxenografts models were used as an in vivo pre-clinical platform to test several treatment strategies. Results: MPNST orthoxenografts recapitulate the histopathological properties and preserve the genomic and transcriptomic status of their parental primary tumors. Additionally, they mimic distal dissemination properties in mice. Compatible with an origin in a catastrophic event and subsequent stabilization, MPNSTs contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Although preliminary, the results presented here point to clear differences between NF1-associated and sporadic MPNSTs. In accordance, mutation frequency in sporadic MPNSTs was an order of magnitude higher than in NF1-associated MPNSTs and unsupervised cluster analysis and principal component analysis (PCA) using a MPNST signature perfectly divided the samples between NF1 and sporadic MPNST. Finally, different therapeutic approaches tested in the validated orthoxenograft MPNST models, reveal that sorafenib, or in combination with doxorubicin or rapamycin caused a great tumor reduction in all models. Conclusion: The development of a well-characterized and standardized preclinical model for MPNSTs has laid the foundations for evaluating novel therapeutic strategies in the clinical setting. Moreover, results obtained strongly support the clinical evaluation of Sorafenib in this subset of patients. Primary MPNSTs were implanted in the sciatic nerve of nude mices to create orthoxenograft MPNST models. Several orthoxenograft passages were created. The primary tumor (when available) and passages 1 and 4 were selected for gene expression profiling to demonstrate that the orthoxenografts closely resemble their primary tumors and are stable along xenograft passages.
2015-04-15 | E-GEOD-60082 | biostudies-arrayexpress