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1.
Nat Commun ; 15(1): 7873, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251601

RESUMO

Meningiomas are associated with inactivation of NF2/Merlin, but approximately one-third of meningiomas with favorable clinical outcomes retain Merlin expression. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that may be used to guide treatment de-escalation or imaging surveillance are lacking. Here, we use single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma xenografts and patients to define biochemical mechanisms and an imaging biomarker that underlie Merlin-intact meningiomas. We find Merlin serine 13 (S13) dephosphorylation drives meningioma Wnt signaling and tumor growth by attenuating inhibitory interactions with ß-catenin and activating the Wnt pathway. MRI analyses show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC). These results define mechanisms underlying a potential imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with Merlin-intact meningiomas.


Assuntos
Imageamento por Ressonância Magnética , Neoplasias Meníngeas , Meningioma , Neurofibromina 2 , Via de Sinalização Wnt , Meningioma/diagnóstico por imagem , Meningioma/metabolismo , Meningioma/patologia , Meningioma/genética , Humanos , Fosforilação , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Animais , Imageamento por Ressonância Magnética/métodos , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/genética , Camundongos , Linhagem Celular Tumoral , beta Catenina/metabolismo , beta Catenina/genética , Feminino , Serina/metabolismo , Masculino , Proteômica/métodos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética
2.
EMBO Rep ; 25(9): 4033-4061, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39160347

RESUMO

Cells sense and respond to various mechanical forces from the extracellular matrix primarily by modulating the actin cytoskeleton. Mechanical forces can be translated into biochemical signals in a process called mechanotransduction. Yes-associated protein (YAP) is an effector of Hippo signaling and a mediator of mechanotransduction, but how mechanical forces regulate Hippo signaling is still an open question. We propose that retinoic acid-induced protein 14 (RAI14) responds to mechanical forces and regulates Hippo signaling. RAI14 positively regulates the activity of YAP. RAI14 interacts with NF2, a key component of the Hippo pathway, and the interaction occurs on filamentous actin. When mechanical forces are kept low in cells, NF2 dissociates from RAI14 and filamentous actin, resulting in increased interactions with LATS1 and activation of the Hippo pathway. Clinical data show that tissue stiffness and expression of RAI14 and YAP are upregulated in tumor tissues and that RAI14 is strongly associated with adverse outcome in patients with gastric cancer. Our data suggest that RAI14 links mechanotransduction with Hippo signaling and mediates Hippo-related biological functions such as cancer progression.


Assuntos
Via de Sinalização Hippo , Mecanotransdução Celular , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Proteínas de Sinalização YAP/metabolismo , Actinas/metabolismo , Ligação Proteica , Fosfoproteínas/metabolismo , Fosfoproteínas/genética
3.
Science ; 385(6709): eadf4478, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39116228

RESUMO

Despite recent studies implicating liquid-like biomolecular condensates in diverse cellular processes, many biomolecular condensates exist in a solid-like state, and their function and regulation are less understood. We show that the tumor suppressor Merlin, an upstream regulator of the Hippo pathway, localizes to both cell junctions and medial apical cortex in Drosophila epithelia, with the latter forming solid-like condensates that activate Hippo signaling. Merlin condensation required phosphatidylinositol-4-phosphate (PI4P)-mediated plasma membrane targeting and was antagonistically controlled by Pez and cytoskeletal tension through plasma membrane PI4P regulation. The solid-like material properties of Merlin condensates are essential for physiological function and protect the condensates against external perturbations. Collectively, these findings uncover an essential role for solid-like condensates in normal physiology and reveal regulatory mechanisms for their formation and disassembly.


Assuntos
Condensados Biomoleculares , Proteínas de Drosophila , Drosophila melanogaster , Via de Sinalização Hippo , Neurofibromina 2 , Animais , Membrana Celular/metabolismo , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Junções Intercelulares/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Condensados Biomoleculares/metabolismo
5.
Development ; 151(14)2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39077779

RESUMO

The Hippo pathway plays a crucial role in cell proliferation and differentiation during tumorigenesis, tissue homeostasis and early embryogenesis. Scaffold proteins from the ezrin-radixin-moesin (ERM) family, including neurofibromin 2 (NF2; Merlin), regulate the Hippo pathway through cell polarity. However, the mechanisms underlying Hippo pathway regulation via cell polarity in establishing outer cells remain unclear. In this study, we generated artificial Nf2 mutants in the N-terminal FERM domain (L64P) and examined Hippo pathway activity by assessing the subcellular localization of YAP1 in early embryos expressing these mutant mRNAs. The L64P-Nf2 mutant inhibited NF2 localization around the cell membrane, resulting in YAP1 cytoplasmic translocation in the polar cells. L64P-Nf2 expression also disrupted the apical centralization of both large tumor suppressor 2 (LATS2) and ezrin in the polar cells. Furthermore, Lats2 mutants in the FERM binding domain (L83K) inhibited YAP1 nuclear translocation. These findings demonstrate that NF2 subcellular localization mediates cell polarity establishment involving ezrin centralization. This study provides previously unreported insights into how the orchestration of the cell-surface components, including NF2, LATS2 and ezrin, modulates the Hippo pathway during cell polarization.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Polaridade Celular , Proteínas do Citoesqueleto , Via de Sinalização Hippo , Neurofibromina 2 , Proteínas Serina-Treonina Quinases , Proteínas Supressoras de Tumor , Proteínas de Sinalização YAP , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Animais , Camundongos , Proteínas de Sinalização YAP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Transdução de Sinais , Embrião de Mamíferos/metabolismo , Mutação/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Transporte Proteico , Membrana Celular/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/genética
6.
PLoS One ; 19(7): e0305121, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39083549

RESUMO

Neurofibromatosis type 2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates a number of key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. While PAK1 and PAK2 directly bind Merlin and transmit proliferation and survival signals when Merlin is mutated or absent, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. In this study, we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. Finally, we demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines.


Assuntos
Proliferação de Células , Via de Sinalização Hippo , Neurilemoma , Neurofibromina 2 , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Quinases Ativadas por p21 , Humanos , Neurilemoma/metabolismo , Neurilemoma/genética , Neurilemoma/patologia , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/genética , Proliferação de Células/efeitos dos fármacos , Neurofibromina 2/genética , Neurofibromina 2/deficiência , Neurofibromina 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Apoptose/efeitos dos fármacos , Sinergismo Farmacológico , Neurofibromatose 2/metabolismo , Neurofibromatose 2/genética , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética
7.
Cancer Res Commun ; 4(8): 2133-2146, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38994676

RESUMO

Immunotherapies have demonstrated limited clinical efficacy in malignant mesothelioma treatment. We conducted multiplex immunofluorescence analyses on tissue microarrays (n = 3) from patients with malignant pleural mesothelioma (MPM, n = 88) and malignant peritoneal mesothelioma (MPeM, n = 25). Our study aimed to elucidate spatial distributions of key immune cell populations and their association with lymphocyte activation gene 3 (LAG3), BRCA1-associated protein 1 (BAP1), neurofibromatosis type 2 (NF2), and methylthioadenosine phosphorylase (MTAP), with MTAP serving as a cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/B) surrogate marker. Additionally, we examined the relationship between the spatial distribution of major immune cell types and prognosis and clinical characteristics of patients with malignant mesothelioma. We observed a higher degree of interaction between immune cells and tumor cells in MPM compared with MPeM. Notably, within MPM tumors, we detected a significantly increased interaction between tumor cells and CD8+ T cells in tumors with low BAP1 expression compared with those with high BAP1 expression. To support the broader research community, we have developed The Human Spatial Atlas of Malignant Mesothelioma, containing hematoxylin and eosin and multiplex immunofluorescence images with corresponding metadata. SIGNIFICANCE: Considering the limited therapeutic options available to patients with malignant mesothelioma, there is substantial translational potential in understanding the correlation between the spatial architecture of the malignant mesothelioma tumor immune microenvironment and tumor biology. Our investigation reveals critical cell-cell interactions that may influence the immune response against malignant mesothelioma tumors, potentially contributing to the differential behaviors observed in MPM and MPeM. These findings represent a valuable resource for the malignant mesothelioma cancer research community.


Assuntos
Mesotelioma Maligno , Mesotelioma , Neoplasias Peritoneais , Neoplasias Pleurais , Purina-Núcleosídeo Fosforilase , Microambiente Tumoral , Ubiquitina Tiolesterase , Humanos , Microambiente Tumoral/imunologia , Mesotelioma Maligno/imunologia , Mesotelioma Maligno/patologia , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Masculino , Feminino , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Purina-Núcleosídeo Fosforilase/metabolismo , Purina-Núcleosídeo Fosforilase/genética , Pessoa de Meia-Idade , Ubiquitina Tiolesterase/metabolismo , Mesotelioma/imunologia , Mesotelioma/patologia , Idoso , Proteínas Supressoras de Tumor/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neurofibromina 2/genética , Biomarcadores Tumorais , Prognóstico , Antígenos CD , Linfócitos T CD8-Positivos/imunologia
8.
Pathol Res Pract ; 261: 155459, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39083879

RESUMO

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of RCC classified as a molecularly defined RCC in the fifth edition of the WHO. Most gene alterations in patients with SDH-deficient RCC involve the SDHB subunit, with less involvement of the SDHC, SDHA, and SDHD subunits. Four cases of SDHA-deficient RCC have been reported in the literature, of which one case was associated with an NF2 gene mutation. Herein, we report six novel SDHA-deficient RCC cases, including two cases with NF2 gene mutations. In contrast to the typical morphology of SDH-deficient RCC, the six tumors mainly displayed glandular, sheet-like, or papillary growth patterns with prominent nucleoli (Grades 2-3), among which two cases with NF2 mutations had prominent nucleoli (Grade 3), large transparent vacuoles in the cytoplasm, and a large number of lymphocytes in the stroma. Six tumors showed negative immunohistochemical staining for SDHA and SDHB, and three cases presented with high expression of PD-L1. Second-generation sequencing revealed novel pathogenic somatic SDHA gene mutation and NF2 gene mutations in six and two tumors, respectively. Follow-up data were collected for the six patients with a follow-up time ranging from 7 to 268 months, and all six patients have survived to date. One patient received targeted therapy for tumor metastasis to the lungs after seven months, and another patient with an NF2 gene mutation received immunotherapy for lymph node metastasis revealed during surgery. SDHA-deficient RCCs with NF2 gene mutations have the ability to metastasize but might respond well to immunotherapy. For the first time, we report the largest number of SDHA-deficient RCC cases and comprehensively investigate their clinicopathological and molecular features to provide important guidance for diagnosis and clinical immunotherapy.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Succinato Desidrogenase , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Succinato Desidrogenase/deficiência , Succinato Desidrogenase/genética , Mutação , Adulto , Idoso , Biomarcadores Tumorais/genética , Neurofibromina 2 , Complexo II de Transporte de Elétrons
9.
FASEB J ; 38(13): e23737, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38953724

RESUMO

Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.


Assuntos
Apoptose , Sinalização do Cálcio , Cálcio , Receptores de Inositol 1,4,5-Trifosfato , Neoplasias Meníngeas , Meningioma , Animais , Humanos , Camundongos , Cálcio/metabolismo , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/genética , Meningioma/metabolismo , Meningioma/patologia , Meningioma/genética , Neurofibromina 2
10.
FASEB J ; 38(13): e23809, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38967126

RESUMO

The neurofibromatosis type 2 (NF2) gene, known for encoding the tumor suppressor protein Merlin, is central to the study of tumorigenesis and associated cellular processes. This review comprehensively examines the multifaceted role of NF2/Merlin, detailing its structural characteristics, functional diversity, and involvement in various signaling pathways such as Wnt/ß-catenin, Hippo, TGF-ß, RTKs, mTOR, Notch, and Hedgehog. These pathways are crucial for cellular growth, proliferation, and differentiation. NF2 mutations are specifically linked to the development of schwannomas, meningiomas, and ependymomas, although the precise mechanisms of tumor formation in these specific cell types remain unclear. Additionally, the review explores Merlin's role in embryogenesis, highlighting the severe developmental defects and embryonic lethality caused by NF2 deficiency. The potential therapeutic strategies targeting these genetic aberrations are also discussed, emphasizing inhibitors of mTOR, HDAC, and VEGF as promising avenues for treatment. This synthesis of current knowledge underscores the necessity for ongoing research to elucidate the detailed mechanisms of NF2/Merlin and develop effective therapeutic strategies, ultimately aiming to improve the prognosis and quality of life for individuals with NF2 mutations.


Assuntos
Carcinogênese , Neurofibromina 2 , Humanos , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Neurofibromatose 2/genética , Neurofibromatose 2/metabolismo , Neurofibromatose 2/patologia , Transdução de Sinais , Mutação
11.
J Pathol ; 264(2): 129-131, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39072755

RESUMO

In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Neurofibromina 2/genética , Proteínas de Fusão Oncogênica/genética , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Receptor trkA/genética , Receptor trkA/metabolismo , Transdução de Sinais/genética , Indazóis/uso terapêutico , Indazóis/farmacologia , Mutação , Sarcoma/genética , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
13.
J Med Genet ; 61(9): 856-860, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-38925914

RESUMO

OBJECTIVES: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed. METHODS: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed. RESULTS: 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1-related schwannomatosis and SMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2. CONCLUSIONS: This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.


Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromatose 2 , Neurofibromina 2 , Proteína SMARCB1 , Neoplasias Cutâneas , Humanos , Neurilemoma/genética , Neurilemoma/epidemiologia , Neurilemoma/patologia , Neurofibromatoses/genética , Neurofibromatoses/epidemiologia , Neurofibromatoses/patologia , Neurofibromatose 2/genética , Neurofibromatose 2/epidemiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Masculino , Feminino , Proteína SMARCB1/genética , Neurofibromina 2/genética , Fatores de Transcrição/genética , Prevalência , Adulto , Mutação/genética , Pessoa de Meia-Idade , Predisposição Genética para Doença , Adolescente
15.
Nat Commun ; 15(1): 5115, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38879607

RESUMO

Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are 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 Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.


Assuntos
Sistemas CRISPR-Cas , Coenzima A Ligases , Glucosefosfato Desidrogenase , Neurofibromina 2 , Células de Schwann , Mutações Sintéticas Letais , Células de Schwann/metabolismo , Humanos , Glucosefosfato Desidrogenase/metabolismo , Glucosefosfato Desidrogenase/genética , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Animais , Neurofibromatose 2/metabolismo , Neurofibromatose 2/genética , NADP/metabolismo , Camundongos , Oxirredução
16.
Artigo em Russo | MEDLINE | ID: mdl-38884429

RESUMO

OBJECTIVE: To identify the characteristics of pain syndrome in patients with schwannomas depending on genetic predisposition. MATERIAL AND METHODS: The study included 46 patients with peripheral, spinal and intracranial schwannomas, corresponding to the schwannomatosis phenotype according to the 2022 clinical criteria. All patients underwent sequencing of the LZRT1, Nf2 and SMARCB1 and a copy number study in the NF2. RESULTS: The most severe widespread pain was observed in patients with pathogenic LZRT1 variants, while patients with mosaic variants may not even have local tumor-related pain. Patients with SMARCB1variants may have no pain or have localized pain that responds well to surgical treatment. CONCLUSION: Further studies of the molecular features of schwannomatosis and driver mutations in the pathogenesis of pain are necessary to improve the effectiveness of pain therapy in this group of patients. Schwannomatosis is a disease from the group of neurofibromatosis, manifested by the development of multiple schwannomas. Neuropathic pain is one of the main symptoms characteristic of peripheral schwannomas, however, the severity and prevalence of the pain syndrome does not always correlate with the location of the tumors. According to modern concepts, the key factors influencing the characteristics of the pain syndrome are the target gene and the type of pathogenic variant. The most severe widespread pain is observed in patients with pathogenic variants in the LZRT1 gene, while patients with mosaic variants may not even have local pain associated with tumors. Patients with variants in SMARCB1 may have no pain or localized pain that responds well to surgical treatment.


Assuntos
Neurilemoma , Neurofibromatoses , Proteína SMARCB1 , Humanos , Neurilemoma/genética , Neurilemoma/complicações , Neurilemoma/diagnóstico , Neurofibromatoses/complicações , Neurofibromatoses/genética , Masculino , Feminino , Adulto , Proteína SMARCB1/genética , Pessoa de Meia-Idade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/complicações , Neurofibromina 2/genética , Fatores de Transcrição/genética , Mutação , Neuralgia/genética , Neuralgia/etiologia , Neuralgia/diagnóstico , Predisposição Genética para Doença , Adulto Jovem
17.
Int J Mol Sci ; 25(12)2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38928264

RESUMO

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.


Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromina 2 , Neoplasias Cutâneas , Humanos , Neurofibromatoses/terapia , Neurofibromatoses/genética , Neurofibromatoses/metabolismo , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Neurilemoma/genética , Neurilemoma/terapia , Neurilemoma/metabolismo , Neurilemoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Animais , Neurofibromatose 2/genética , Neurofibromatose 2/terapia , Neurofibromatose 2/metabolismo , Mutação , Transdução de Sinais , Terapia de Alvo Molecular
18.
CNS Neurosci Ther ; 30(6): e14784, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38828669

RESUMO

INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. AIMS: The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. RESULTS: PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy. CONCLUSIONS: Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.


Assuntos
Antígeno B7-H1 , Proliferação de Células , Neoplasias Meníngeas , Meningioma , Neurofibromatose 2 , Linfócitos T , Meningioma/metabolismo , Meningioma/imunologia , Meningioma/patologia , Humanos , Antígeno B7-H1/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/imunologia , Animais , Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Neurofibromatose 2/metabolismo , Camundongos , Masculino , Feminino , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Camundongos Nus , Apoptose/efeitos dos fármacos , Apoptose/fisiologia
19.
Commun Biol ; 7(1): 533, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710747

RESUMO

Insect wing development is a fascinating and intricate process that involves the regulation of wing size through cell proliferation and apoptosis. In this study, we find that Ter94, an AAA-ATPase, is essential for proper wing size dependently on its ATPase activity. Loss of Ter94 enables the suppression of Hippo target genes. When Ter94 is depleted, it results in reduced wing size and increased apoptosis, which can be rescued by inhibiting the Hippo pathway. Biochemical experiments reveal that Ter94 reciprocally binds to Mer, a critical upstream component of the Hippo pathway, and disrupts its interaction with Ex and Kib. This disruption prevents the formation of the Ex-Mer-Kib complex, ultimately leading to the inactivation of the Hippo pathway and promoting proper wing development. Finally, we show that hVCP, the human homolog of Ter94, is able to substitute for Ter94 in modulating Drosophila wing size, underscoring their functional conservation. In conclusion, Ter94 plays a positive role in regulating wing size by interfering with the Ex-Mer-Kib complex, which results in the suppression of the Hippo pathway.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Proteínas de Membrana , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Proteínas Supressoras de Tumor , Asas de Animais , Animais , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/genética , Apoptose , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
20.
Glia ; 72(8): 1518-1540, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38794866

RESUMO

In the central nervous system, the formation of myelin by oligodendrocytes (OLs) relies on the switch from the polymerization of the actin cytoskeleton to its depolymerization. The molecular mechanisms that trigger this switch have yet to be elucidated. Here, we identified P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. Our results demonstrate that PAK1 accumulates in OLs in a kinase-inhibited form, triggering actin disassembly and, consequently, myelin membrane expansion. Remarkably, proteomic analysis of PAK1 binding partners enabled the identification of NF2/Merlin as its endogenous inhibitor. Our findings indicate that Nf2 knockdown in OLs results in PAK1 activation, actin polymerization, and a reduction in OL myelin membrane expansion. This effect is rescued by treatment with a PAK1 inhibitor. We also provide evidence that the specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that the antagonistic actions of PAK1 and NF2/Merlin on the actin cytoskeleton of the OLs are critical for proper myelin formation. These findings have broad mechanistic and therapeutic implications in demyelinating diseases and neurodevelopmental disorders.


Assuntos
Bainha de Mielina , Oligodendroglia , Quinases Ativadas por p21 , Quinases Ativadas por p21/metabolismo , Oligodendroglia/metabolismo , Animais , Bainha de Mielina/metabolismo , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Ratos , Actinas/metabolismo , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Citoesqueleto de Actina/metabolismo
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