Similar Datasets
Project description:Characterization of non-NF2 related schwannomatosis
| PRJNA1186708 | ENA
Project description:NF2-related schwannomatosis (NF2-SWN) is a cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas. While benign, these tumors can cause significant morbidity and effective pharmacological treatments remain limited. Here we demonstrate that genetic ablation of focal adhesion kinase 1 (FAK1/PTK2) impairs tumor formation and preserves hearing in a murine model of NF2. Mechanistically, we show that Fak1 deletion decreases macrophage infiltration, attenuates NLRP3 inflammasome activation and suppresses the HGF-MET axis. Pharmacological inhibition of FAK with single agent VS-4718 did not significantly reduce macroscopic tumor volume, however, its use in combination with the MEK inhibitor selumetinib resulted in both a significant reduction tumor volume and the preservation of dorsal root ganglion (DRG) architecture. Our findings establish a critical role for FAK in schwannoma development and provide rationale for evaluation of combination FAK plus MEK inhibition in future clinical trials for NF2-associated schwannomas.
2025-09-17 | GSE292315 | GEO
Project description:We previously generated an orthotopic, NF2-deficient meningioma model using the luciferase-expressing Ben-Men-1 cell line established from a sporadic tumor and identified the multi-kinase inhibitor brigatinib and the mTOR kinase inhibitor INK128 to potently impede tumor growth. Here, we describe generation of the telomerase-immortalized AG-NF2-Men cell line from a grade-1 meningioma of an NF2-related schwannomatosis (NF2-SWN) patient. We showed that like Ben-Men-1 cells, AG-NF2-Men cells were NF2-null, expressed several NF2-regulated receptor tyrosine kinases, and responded to their cognate ligands. We also found that brigatinib and INK128 alone inhibited AG-NF2-Men cell proliferation at IC50 values similar to those in Ben-Men-1 cells. Combining brigatinib with INK128 exhibited growth-inhibitory synergy. Mechanistically, the combination not only completely abrogated p-AKT(S473) and its downstream signaling compared to either drug alone but also prevented INK128-mediated re-phosphorylation of AKT on T308. Also, the combination more-effectively blocked ligand-mediated phosphorylation of EGFR, ErbB3, and IGF-1R and elicited major changes in the expression of genes including the upstream regulators of several signaling networks important for meningioma growth. Further, we generated luciferase-expressing AG-NF2-Men cells that readily grew as intracranial xenografts. Importantly, combining brigatinib with INK128 enhanced tumor regression in both the orthotopic AG-NF2-Men and Ben-Men-1 xenograft models. As the first NF2-SWN-related meningioma cell line, AG-NF2-Men is a unique reagent for investigating meningioma biology and therapeutics. A clinical trial to evaluate the combination of brigatinib with an mTOR inhibitor in NF2-deficient meningiomas is warranted.
2025-09-05 | GSE307286 | GEO
Project description:Effect of Fak1/Ptk2 knockout in a mouse model of NF2-related schwannomatosis
| PRJNA1237899 | ENA
Project description:Patients with neurofibromatosis type 2-related schwannomatosis (NF2-SWN) develop hallmark tumors on their vestibular nerves, leading to hearing loss and numerous associated morbidities. Currently, there are no targeted therapeutic options for treating these tumors. In prior work, our group had identified brigatinib as a potentially active drug in the treatment of murine models of NF2-SWN and meningioma, leading to a clinical trial in NF2-SWN patients testing brigatinib. Kinome profiling revealed that brigatinib resulted in the inhibition of focal adhesion kinase 1 (FAK1, encoded by the PTK2 gene). To test the contribution of FAK1, we generated a genetically engineered mouse model of NF2-SWN with Fak1/Ptk2 deletion in tumorigenic cells of origin. Genetic ablation of Fak1/Ptk2 preserved hearing in the mice and reduced tumorigenesis. Here we used an immortalized human Schwann cell line, 02.3 2lambda, Control and 3 NF2 KO clones, to perform kinome profiling.
2025-09-19 | PXD068581 | Pride
Project description:Background: Schwannomas are nerve sheath tumors arising at cranial and peripheral nerves, either sporadically or in patients with a schwannomatosis-predisposition syndrome. There is limited understanding of the transcriptional heterogeneity of schwannomas across genetic backgrounds and anatomic locations. Methods: Here, we prospectively profile by single-cell full-length transcriptomics tumors from 22 patients with NF2-related schwannomatosis, non-NF2-related schwannomatosis, and sporadic schwannomas, resected from cranial and peripheral nerves. We profiled 11,373 cells, including neoplastic cells, fibroblasts, T cells, endothelial cells, myeloid cells and pericytes. Results: We characterize the intra-tumoral genetic and transcriptional heterogeneity of schwannoma, identifying six distinct transcriptional metaprograms, with gene signatures related to stress, myelin production, antigen presentation, interferon signaling, glycolysis and extracellular matrix. We demonstrate the robustness of our findings with analysis of an independent cohort. Conclusion: Overall, our atlas describes the spectrum of gene expression across schwannoma entities at the single-cell level and will serve as important resource for the community.
2025-04-17 | GSE292071 | GEO
Project description:NF2-related schwannomatosis (NF2-SWN) is a cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas. While benign, these tumors can cause significant morbidity and effective pharmacological treatments remain limited. Here we demonstrate that genetic ablation of focal adhesion kinase 1 (FAK1/PTK2) impairs tumor formation and preserves hearing in a murine model of NF2. Mechanistically, we show that Fak1 deletion decreases macrophage infiltration, attenuates NLRP3 inflammasome activation and suppresses the HGF-MET axis. Pharmacological inhibition of FAK with single agent VS-4718 did not significantly reduce macroscopic tumor volume, however, its use in combination with the MEK inhibitor selumetinib resulted in both a significant reduction tumor volume and the preservation of dorsal root ganglion (DRG) architecture. Our findings establish a critical role for FAK in schwannoma development and provide rationale for evaluation of combination FAK plus MEK inhibition in future clinical trials for NF2-associated schwannomas.
2025-09-17 | GSE289387 | GEO
Project description:Patients with neurofibromatosis type 2-related schwannomatosis (NF2-SWN) develop hallmark tumors on their vestibular nerves, leading to hearing loss and numerous associated morbidities. Currently, there are no targeted therapeutic options for treating these tumors. In prior work, our group had identified brigatinib as a potentially active drug in the treatment of murine models of NF2-SWN and meningioma, leading to a clinical trial in NF2-SWN patients testing brigatinib. Kinome profiling revealed that brigatinib resulted in the inhibition of focal adhesion kinase 1 (FAK1, encoded by the PTK2 gene). To test the contribution of FAK1, we generated a genetically engineered mouse model of NF2-SWN with Fak1/Ptk2 deletion in tumorigenic cells of origin. Genetic ablation of Fak1/Ptk2 preserved hearing in the mice and reduced tumorigenesis. Here we used an immortalized Nf1 null Schwann cell line, MS03, to perform kinome profiling using the FAK inhibitors defactinib and VS-4718. Kinase enrichment proteomic analysis was performed using MS03 cells treated for 24 h with DMSO control, 1 micromolar defactinib, or 1 micromolar VS-4718 to evaluate the effects on the functional kinome.
2025-09-17 | PXD060730 | Pride
Project description:We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. Analysis of meningioma gene expression data for each mutation subtype. Includes gene expression data from 75 unique meningiomas and 39 replicates.
2014-05-29 | E-GEOD-58037 | biostudies-arrayexpress
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 TR1 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