The transcriptomic signature of painful and non-painful human NF2 schwannomas [set2]
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ABSTRACT:
PROVIDER: PRJNA575540 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10220719_1.fastq.gz | Fastqsanger.gz | |||
| SRR10220719_2.fastq.gz | Fastqsanger.gz | |||
| SRR10220720_1.fastq.gz | Fastqsanger.gz | |||
| SRR10220720_2.fastq.gz | Fastqsanger.gz | |||
| SRR10220721_1.fastq.gz | Fastqsanger.gz |
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Project description:Schwannomas are benign peripheral nerve sheath tumors that are associated with substantial morbidity including severe, persistent pain. Treatment, essentially limited to surgical resection, is associated with significant morbidity and for many patient’s efficacious treatment of tumor-related pain is not achievable. There is an urgent need to elucidate the molecular mechanisms underlying schwannoma-induced pain as a first step in development of new therapeutics. In this study, we performed next-generation RNASequencing on a small cohort of formalin fixed paraffin-embedded, painful, and non-painful schwannoma samples obtained from Neurofibromatosis type 2 (NF2) patients. Differential gene and isoform level expression analysis revealed significant transcriptomic differences between painful and non-painful tumors; differentially regulated genes included members of the fibroblast growth factor (FGF) family of genes. Using a xenograft model of human-NF2 we demonstrated that over-expression of FGF7 in schwannoma cells was associated with the development of pain-like behaviors. These results demonstrate both the value of RNASeq utilizing formalin fixed tissues and reveal a novel pathway responsible for neoplasm-associated pain.
2020-05-01 | GSE138346 | GEO
Project description:The transcriptomic signature of painful and non-painful human NF2 schwannomas
| PRJNA575542 | ENA
Project description:The transcriptomic signature of painful and non-painful human NF2 schwannomas [set1]
| PRJNA575539 | ENA
Project description:Schwannomas are benign peripheral nerve sheath tumors that are associated with substantial morbidity including severe, persistent pain. Treatment, essentially limited to surgical resection, is associated with significant morbidity and for many patient’s efficacious treatment of tumor-related pain is not achievable. There is an urgent need to elucidate the molecular mechanisms underlying schwannoma-induced pain as a first step in development of new therapeutics. In this study, we performed next-generation RNASequencing on a small cohort of formalin fixed paraffin-embedded, painful, and non-painful schwannoma samples obtained from Neurofibromatosis type 2 (NF2) patients. Differential gene and isoform level expression analysis revealed significant transcriptomic differences between painful and non-painful tumors; differentially regulated genes included members of the fibroblast growth factor (FGF) family of genes. Using a xenograft model of human-NF2 we demonstrated that over-expression of FGF7 in schwannoma cells was associated with the development of pain-like behaviors. These results demonstrate both the value of RNASeq utilizing formalin fixed tissues and reveal a novel pathway responsible for neoplasm-associated pain.
2020-05-01 | GSE138344 | GEO
Project description:Treatment of multiple intracranial schwannomas in patient with neurofibromatosis type 2 (NF2) is extremely unsatisfactory and innovative therapeutic approaches are urgently needed. The lack of clinically relevant NF2 models has severely hampered drug discovery in this rare disease. Here, we report for the first time the establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which retain the gene mutations and transcriptome profile, and recapitulate the morphological and histopathological features with the patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling the patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannoma. Using expression profiling, we found that the PI3K/AKT/mTOR networks are elevated in NF2-associated vestibular schwannomas, as well as in PDX models.
2022-04-04 | GSE180338 | GEO
Project description:Neurofibromatosis type 2 is an inherited neoplastic disease consisting of schwannomas, meningiomas, and ependymomas that is caused by inactivation of the tumor suppressor gene NF2. The NF2 gene product, merlin, has no intrinsic catalytic activity; its tumor suppressor function is mediated through the proteins with which it interacts. However, there is no consensus about which merlin interactions are necessary for tumor suppression. We used proximity biotinylation followed by mass spectrometry and direct binding assays to characterize the proteins that associate with merlin and merlin mutants in immortalized Schwann cells. We identified 52 proteins that associate with merlin, including a previously unreported merlin binding protein, ASPP2. Our results identify merlin as a component of mechanosensing signal transduction pathways in cell junctions, in the context of a specific set of structures and molecules through which it acts, in a cell type relevant to schwannoma formation.
2019-04-25 | PXD012017 | Pride
Project description:Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth cause progressive hearing loss, and the standard treatment including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allows hearing test. Here we developed a cerebellopontine angle (CPA) schwannomas model that faithfully recapitulates the tumor-induced hearing loss. Using this model we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor HGF levels. cMET gene knockdown study independently confirmed the role of cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared to normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in NF2 patients. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared to normal nerves, which correlated with tumor growth and cyst formation.
2018-06-26 | GSE108524 | GEO
Project description:Vestibular Schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of NF2. Transcriptomic alterations, such as the Nrg1/ErbB2 pathway, have been described in Schwannomas. Here, we have performed a whole transcriptomic analysis in 31 vestibular Schwannomas and 9 control nerves in the Affymetrix Gene 1.0ST platform, validated by quantitative Real-Time PCR using TaqMan Low Density Arrays. We performed a mutational analysis of NF2 by PCR/dHPLC and MLPA as well as a microsatellite marker analysis of the loss of heterozygosity of chromosome 22q. The microarray analysis showed that 1516 genes were deregulated, and 48 of the genes were validated by qRT-PCR. At least two genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed one hit and eight tumors showed no NF2 alteration. As conclusion, MET and associated genes such as ITGA4/B6, PLEXNB3/SEMA5 and CAV1 showed a clear deregulation in vestibular Schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in Merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in Schwannoma Merlin depletion. Finally, no major differences were found between tumors of different sizes, histological types or NF2 status, which suggests that at the mRNA level all Schwannomas, regardless of molecular and clinical characteristics, may share common features that can be used in the fight against them. In order to find target to fight against vestibular schwannoma, we performed an analysis of gene expression by microarrays.
2013-03-01 | E-GEOD-39645 | biostudies-arrayexpress
Project description:We developed Ab12 cells with reduced levels of Nf2 by usin shRNA
2021-09-30 | GSE156620 | GEO
Project description:Background: Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disease characterized by the development of multiple Schwannomas, usually occurring on both VIIIth (vestibular) cranial nerves. Bromodomain and extra-terminal domain (BET) proteins regulate gene transcription and their activity is required in a variety of cancers including malignant peripheral nerve sheath tumors (MPNST). The use of BET inhibitors as a therapeutic option to treat NF2 schwannomas has not been explored and is the focus of this study. Methods: A panel of normal and NF2-null Schwann cell and schwannoma cell lines were used to characterize the impact of the BET inhibitor JQ1 in vitro and in vivo. The mechanism of action was explored by chromatin immunoprecipitation (ChIP) of the BET BRD4, phospho-kinase arrays and immunohistochemistry of BRD4 in human vestibular schwannomas. Results: JQ1 inhibited the proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo. Further, loss of NF2 by CRISPR deletion or siRNA knockdown increased the sensitivity of cells to JQ1. Knock-down experiments identified BRD4 as the BET family member mediating the majority of JQ1 effects on cell proliferation. Immunohistochemistry demonstrated elevated levels of BRD4 protein in human vestibular schwannomas. BRD4 ChIP experiments identified the small G-protein Rac1 and PI3K signaling pathways as sensitive to JQ1. Conclusions: NF2 deficient Schwann cell and schwannoma cells are sensitive to BET inhibition, primarily mediated by BRD4, which is overexpressed in human vestibular schwannomas. BRD4 regulates Rac/Ras and PI3K signaling pathways and inhibition of these pathways by JQ1 impedes NF2 Schwannoma growth. These findings implicate BET inhibition as a therapeutic option for NF2-deficient schwannomas.
2022-08-02 | GSE167560 | GEO