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Functional Merlin Depletion Defines a TEAD1-Dependent Tumor Cell State that Promotes Schwannoma Progression: bulk methylation

ABSTRACT: Biallelic loss of the tumor suppressor NF2/merlin drives vestibular schwannomas (VS). Intratumoral heterogeneity has been observed in VS at the transcriptional, protein expression, and cellular proliferative potential levels, highlighting the need to elucidate the mechanisms underlying heterogeneity in tumor Schwann cell merlin inactivation and therapeutic resistance. Using integrated single-cell multi-omic profiling across NF2-related (VSnf2) and sporadic (VSspo) schwannomas, we identified functional merlin depletion as a continuous, spatially organized, plastic tumor Schwann cell state, rather than a binary genetic event. A transcriptomic merlin depletion score (MDS) captured this gradient, and merlin-depleted tumor Schwann cells were identified as a potential source of proliferative, angiogenic, and macrophage-recruiting signals. Lineage trajectory and multi-omic regulatory modeling identified the transcription factor TEAD1 as a potential regulator of MDS states and signaling pathways underlying tumor progression. Pharmacologic TEAD auto-palmitoylation inhibitors disrupted TEAD1–YAP/TAZ interactions, reversed merlin-loss transcriptional programs, suppressed VEGFA, NRG1, IL-34, and CSF1 signaling, and selectively attenuated tumor cell viability in human Schwann tumor cultures and in a mouse model. Overall, these findings show that merlin-loss heterogeneity is a functional, targetable axis in schwannoma and that TEAD1 inhibition could be a potentially useful therapeutic strategy for NF2/merlin depleted tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE345131 | GEO | 2026/09/25

REPOSITORIES: GEO

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Functional Merlin Depletion Defines a TEAD1-Dependent Tumor Cell State that Promotes Schwannoma Progression: Xenium spatial transcriptomics

Project description:Biallelic loss of the tumor suppressor NF2/merlin drives vestibular schwannomas (VS). Intratumoral heterogeneity has been observed in VS at the transcriptional, protein expression, and cellular proliferative potential levels, highlighting the need to elucidate the mechanisms underlying heterogeneity in tumor Schwann cell merlin inactivation and therapeutic resistance. Using integrated single-cell multi-omic profiling across NF2-related (VSnf2) and sporadic (VSspo) schwannomas, we identified functional merlin depletion as a continuous, spatially organized, plastic tumor Schwann cell state, rather than a binary genetic event. A transcriptomic merlin depletion score (MDS) captured this gradient, and merlin-depleted tumor Schwann cells were identified as a potential source of proliferative, angiogenic, and macrophage-recruiting signals. Lineage trajectory and multi-omic regulatory modeling identified the transcription factor TEAD1 as a potential regulator of MDS states and signaling pathways underlying tumor progression. Pharmacologic TEAD auto-palmitoylation inhibitors disrupted TEAD1–YAP/TAZ interactions, reversed merlin-loss transcriptional programs, suppressed VEGFA, NRG1, IL-34, and CSF1 signaling, and selectively attenuated tumor cell viability in human Schwann tumor cultures and in a mouse model. Overall, these findings show that merlin-loss heterogeneity is a functional, targetable axis in schwannoma and that TEAD1 inhibition could be a potentially useful therapeutic strategy for NF2/merlin depleted tumors.

2026-09-25 | GSE345691 | 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

Microarray Analysis in Vestibular Schwannomas

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

Merlin/NF2-loss Driven Tumorigenesis Linked to CRL4(DCAF1)-Mediated Inhibition of the Hippo Pathway Components Lats1 and 2

Project description:Studies in drosophila have suggested that Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at or near the plasma membrane. In contrast, studies of Merlin-deficient tumor cells have indicated that Merlin suppresses tumorigenesis by entering into the nucleus where it inhibits the E3 ubiquitin ligase CRL4DCAF1. We found that CRL4DCAF1 promotes YAP and TEAD-dependent transcription by ubiquitylating and thereby inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2 mutant mesotheliomas, schwannomas and meningiomas. We conclude that de-repressed CRL4DCAF1 controls the output of the Hippo pathway by inhibiting Lats1 and 2 in the nucleus.

2014-07-15 | GSE56157 | GEO

Microarray Analysis in Vestibular Schwannomas

2013-03-01 | GSE39645 | 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

Analysis of the transcriptomic profile of WT mouse embryonic fibroblast (MEF WT) and Nf2-knockout mouse embryonic fibroblast (MEF Nf2 KO) cell lines

Project description:Merlin is the tumor suppressor protein encoded by the NF2 gene. The expression of Merlin is remarkably decreased in metastatic breast cancer tissues irrespective of the breast cancer subtype. In order to ascribe clinical relevance, we re-capitulated the loss of Merlin in breast cancer cells. Merlin deficiency elicited a markedly invasive phenotype. In order to overcome the challenge of embryonic lethality of a total Nf2-knockout, we generated a unique mammary-specific Nf2-knockout mouse mammary tumor model. Both, the Nf2-knockout mouse embryonic fibroblasts (MEF) and Merlin-deficient breast tumor cells displayed a robust invasive phenotype. Transcriptomic assessment of Nf2-knockout MEFs revealed notable alterations in glutathione transferase and antioxidant networks indicating a role for Merlin in redox biology. This programmatic alteration resonated with the pathways that emerged from breast tumor cells engineered for Merlin deficiency.

2021-04-14 | GSE157677 | GEO

Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus

Project description:Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4DCAF1, and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 induce a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlinâs ability to interact with or inhibit CRL4DCAF1. Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1. To examine if Merlin controls gene expression through inhibition of CRL4DCAF1, and define the general function of this ligase, we compared the gene expression program activated by expression of Merlin or by depletion of DCAF1 in Merlin-null FC-1801 mouse Schwannoma cells

2010-03-09 | E-GEOD-19305 | biostudies-arrayexpress

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

Project description: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.

2021-10-22 | GSE186107 | GEO

Global expression profile in a combined study in low grade meningiomas and schwannomas shows upregulation in PDGF, CDH1, SLIT2 and MET.

Project description:Background: Schwannomas and grade I meningiomas are non-metastatic neoplasms that shares the common mutation of gene NF2. They usually appear in Neurofibromatosis type 2 patients. Currently, there is no drug treatment available for both tumors, so the use of wide expression technologies is crucial to find those therapeutic targets. Methodology: Affymetrix Human Gene 1.0 ST was used to test global gene expression in 22 meningiomas, 31 schwannomas and, as non-tumoral controls, 3 healthy meningeal tissues, 8 non-tumoral nerves and 1 primary Schwann cells culture. A non-stringent P-cutoff and fold change were used to establish deregulated genes. Results and discussion: We found a subset of genes that were upregulated in meningiomas and schwannomas when compared to their respectively healthy tissue, including PDGFD, CDH1, SLIT2 and MET. Thus, those genes could be more thoroughly studied as targets in a possible combined treatment. Methodology: Affymetrix Human Gene 1.0 ST was used to test global gene expression in 22 meningiomas, 31 schwannomas and, as non-tumoral controls, 3 healthy meningeal tissues, 8 non-tumoral nerves and 1 primary Schwann cells culture. A non-stringent P-cutoff and fold change were used to establish deregulated genes.

2015-08-30 | E-GEOD-54934 | biostudies-arrayexpress

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