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High-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling.

ABSTRACT: Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263122 | GEO | 2024/08/26

REPOSITORIES: GEO

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Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice [mouse]

Project description:We analyzed the expression profiles of human and mouse meningiomas (driven by NF2 loss, YAP1-MAML2, TRAF7/KLF4/SMO1/AKT1, or constitutively active non-fusion YAP1). We found that YAP1-MAML2 meningiomas resemble NF2mutant tumors and constitutively exert de-regulated YAP1 activity that is dependent on the interaction with TEADs.

2022-09-02 | GSE199562 | GEO

Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice [human]

2022-09-02 | GSE199549 | GEO

"Immunogenic subtype" characterised by macrophages infiltration predominantly comprise meningiomas in neurofibromatosis type 2 patients

Project description:Aims: Whereas recent molecular analysis has revealed that sporadic meningioma has various genetic, epigenetic, and transcriptomic profiles, those of meningioma in NF2 patients are not fully elucidated. This study probed meningiomas' clinical, histological, and molecular characteristics in NF2 patients. Methods: A long-term retrospective follow-up (13.5 ± 5.5 years) study involving 159 meningiomas in NF2 patients was performed. We assessed their characteristics by performing immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in NF2 patients were compared with those of 189 sporadic NF2-altered meningiomas. Results: Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/yr. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade 1 meningiomas in NF2 patients` were more frequent than in sporadic NF2-altered meningiomas (92.9% vs 80.9%). Transcriptomic analysis for NF2 patients`/sporadic NF2-altered WHO grade 1 meningiomas (n = 14 versus 15, respectively) showed that tumours in NF2 patients had still higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this higher immune response by identifying myeloid cell infiltration, especially macrophages. Conclusions: Clinical, histological, and transcriptomic analyses for meningiomas in NF2 patients demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited marked immune response by identifying myeloid cell infiltration, especially macrophages.

2023-08-08 | GSE232528 | GEO

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

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

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

2014-05-29 | GSE58037 | GEO

Merlin S13 phosphorylation controls meningioma Wnt signaling and magnetic resonance imaging features

Project description:Meningiomas are the most common primary intracranial tumors and are associated with inactivation of the tumor suppressor NF2/Merlin, but one-third of meningiomas retain Merlin expression and typically have favorable clinical outcomes. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that predict meningioma outcomes and could be used to guide treatment de-escalation or imaging surveillance of Merlin-intact meningiomas are lacking. Here we integrate single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma cells, xenografts, and human patients to define biochemical mechanisms and an imaging biomarker that distinguish Merlin-intact meningiomas with favorable clinical outcomes from meningiomas with unfavorable clinical outcomes. We find Merlin drives meningioma Wnt signaling and tumor growth through a feed-forward mechanism that requires Merlin dephosphorylation on serine 13 (S13) to attenuate inhibitory interactions with β-catenin and activate the Wnt pathway. Meningioma MRI analyses of xenografts and human patients show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC) on diffusionweighted imaging. In sum, our results shed light on Merlin posttranslational modifications that regulate meningioma Wnt signaling and tumor growth in tumors without NF2/Merlin inactivation. To translate these findings to clinical practice, we establish a non-invasive imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with favorable meningiomas.

2024-07-04 | PXD053578 | Pride

Genomic Characterization of Meningiomas

Project description:<p>Meningiomas are the most common primary brain tumor in the US. Although the tumor suppressor gene NF2 is disrupted in approximately half of meningiomas, the complete spectrum of genetic changes in meningiomas remains poorly understood, particularly in the large subset of tumors without NF2 alterations. Therefore we performed whole-genome sequencing from 11 Grade I meningioma tumor-normal pairs and whole-exome sequencing from an additional 6 tumor-normal pairs to identify somatic mutations, insertions-deletions, copy-number alterations and rearrangements. We validated our results by performing focused sequencing across 48 additional meningiomas.</p>

| phs000552 | dbGaP

RNA-seq data set of EGFR mutant human non-small cell lung cancer cell lines PC9, HCC827, HCC4006 after NF2 knockout, YAP1 or WWTR1 overexpression or osimertinib treatment

Project description:Experiment was designed to study the effect of Hippo pathway on osimertinib resistance in non-small cell lung cancer cell lines. The specific comparisons investigated were: PC-9: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE, EV DMSO treated vs EV osimertinib treated HCC827: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE,EV DMSO treated vs EV osimertinib treated HCC4006: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE, EV DMSO treated vs EV osimertinib treated

2024-07-01 | E-MTAB-13831 | biostudies-arrayexpress

Integrated genomic analyses of de novo pathways underlying atypical meningiomas [miRNA-seq]

Project description:Meningiomas are mostly benign brain tumors, with a potential for becoming atypical or malignant. Based on comprehensive genomic, transcriptomic and epigenomic analyses of meningiomas, we compared benign tumors to atypical ones. We show that the vast majority of primary (de novo atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent mutations in SMARCB1. These tumors harbor increased H3K27me3 repressive signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2 binding sites in human embryonic stem cells (hESCs, thereby phenocopying a more primitive cellular state. Consistent with this observation, and based on differential gene expression analysis as well as correlation of mRNA:miRNA regulatory networks, atypical meningiomas exhibit up-regulation of EZH2, the catalytic subunit of the PRC2 complex, well as the E2F2 and FOXM1 transcriptional networks that promote proliferation through activation of the cell cycle pathways. In addition, based on H3K27ac ChIP-seq analysis, we show atypical tumors to display an activated super-enhancer near the meningeal identity transcription factor ZIC1, leading to its transcriptional upregulation. Importantly, these primary atypical meningiomas do not harbor activating TERT promoter mutations, which have been reported in atypical tumors that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas, differentiating their profile from benign and progressed tumors and establishing novel therapeutic targets.

2017-01-12 | GSE93519 | GEO

Integrated genomic analyses of de novo pathways underlying atypical meningiomas [methylation]

Project description:Meningiomas are mostly benign brain tumors, with a potential for becoming atypical or malignant. Based on comprehensive genomic, transcriptomic and epigenomic analyses of meningiomas, we compared benign tumors to atypical ones. We show that the vast majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent mutations in SMARCB1. These tumors harbor increased H3K27me3 repressive signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells (hESCs), thereby phenocopying a more primitive cellular state. Consistent with this observation, and based on differential gene expression analysis as well as correlation of mRNA:miRNA regulatory networks, atypical meningiomas exhibit up-regulation of EZH2, the catalytic subunit of the PRC2 complex, well as the E2F2 and FOXM1 transcriptional networks that promote proliferation through activation of the cell cycle pathways. In addition, based on H3K27ac ChIP-seq analysis, we show atypical tumors to display an activated super-enhancer near the meningeal identity transcription factor ZIC1, leading to its transcriptional upregulation. Importantly, these primary atypical meningiomas do not harbor activating TERT promoter mutations, which have been reported in atypical tumors that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas, differentiating their profile from benign and progressed tumors and establishing novel therapeutic targets.

2016-12-20 | GSE91375 | GEO

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