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Gene expression changes in HEI-193 (NF2-deficient Schwannoma) cells by Nf18001 or TEW7197 treatment.

ABSTRACT: Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGF- receptor 2 (TR2) expression and reduction or loss of NF2 activated non-canonical TGF- signaling, which reduced RKIP expression via TR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGF- signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST. To know the global effect of Nf18001, we performed the microarray with HEI-193.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186107 | GEO | 2021/10/22

REPOSITORIES: GEO

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Gene expression changes in HEI-193 (NF2-deficient Schwannoma) cells by NF2-restoring or TEW7197 treatment.

Project description:Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease and until now, it’s proper treatment has not been suggested. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGF-β receptor 2 (TβR2) expression and an overwhelming expression of TGF-β receptor 1 is activated by physical stimuli such as pressure or heavy materials. Activated TR1 induced the phosphorylation and degradation of RKIP. RKIP reduction consequently results in MAPK activation as well as Snail-mediated p53 suppression and occurrence of EMT in NF2-deficient cells by physical stimuli. Thus, TβR1 kinase inhibitors restore cell differentiation and induce growth suppression in NF2 deficient Schwannoma cell line and MEF. Moreover, TEW7197, a specific TβR1 kinase inhibitor, reduces tumor formation in the NF2-model mouse (Postn-Cre;NF2f/f). Gene expression profiling reveals that TEW7197-treatment induces the expression of lipid metabolism-related gene set such as NF2-restored cells in HEI-193 (NF2-deficient Schwannoma). Our results indicate that reduction or deletion of TβR2 or NF2 induces the TβR1-mediated oncogenic pathway, and therefore inhibition of the unbalanced TGF-β signaling is a putative strategy for NF2-related cancers (NF2 syndrome and mesothelioma) and TβR2 mutated advanced cancers. To know the global effect of TEW7197, we performed the microarray with HEI-193.

2018-06-06 | GSE115359 | GEO

Chip of BRD4 in Neurofibromatosis type 2

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

Proteomic analysis of the NF2/Merlin Interactome by Proximity Biotinylation

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

Integrative genomic analyses of neurofibromatosis tumors identify SOX9 as biomarker and survival gene

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

Treatment of Novel Patient-Derived Xenograft and Cell Line Models with PI3K/AKT/mTOR Inhibitors Revealed Treatment Response Heterogeneity in NF2-Associated Schwannoma

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

Integrative genomic analyses of neurofibromatosis tumors identify SOX9 as biomarker and survival gene

2009-07-15 | GSE14038 | GEO

Transgenic mice overexpressing Neuregulin-1 model neurofibroma-malignant peripheral nerve sheath tumor progression and implicate specific chromosomal copy number variations in tumorigenesis.

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

Screen for genes showing synthetic lethality with NF2 in Schwannoma [Other]

Project description:Neurofibromatosis Type II is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent growth of benign tumors from Schwann cells, the glia of the peripheral nervous system. Unfortunately, no pharmacological therapy is currently available for NFII. Here, we undertake a genome-wide CRISPR/cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant cells but not NF2 wildtype cells. We thereby identify ACSL3 and G6PD as two synthetic-lethal partners for NF2. We find that NF2 mutant Schwann cells are vulnerable to G6PD inhibition because they have low levels of ME1. G6PD and ME1 redundantly generate cytosolic NADPH needed by cells to fight oxidative stress. Lack of either one of the two is compatible with cell viability, but down-regulation of both leads to Schwann cell death. Since genetic deficiency for G6PD is tolerated in the human population, this raises the possibility that G6PD could be a pharmacological target for NFII.

2024-04-24 | GSE219136 | GEO

Screen for genes showing synthetic lethality with NF2 in Schwannoma [RNA-Seq]

2024-04-24 | GSE219135 | GEO

The transcriptomic signature of painful and non-painful human NF2 schwannomas [set2]

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

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