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1.
Neurology ; 93(10): e964-e967, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31363058

RESUMO

OBJECTIVE: To educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children. METHODS: A retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed. RESULTS: The average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%). CONCLUSIONS: Although uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management.


Assuntos
Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromina 2/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
2.
Dev Cell ; 49(3): 425-443.e9, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31063758

RESUMO

Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome neurofibromatosis type 2 (NF2), as well as various sporadic cancers including kidney cancer. Multiple Merlin/NF2 effector pathways including the Hippo-YAP/TAZ pathway have been identified. However, the molecular mechanisms underpinning the growth and survival of NF2-mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors. Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and reactive oxygen species (ROS) buildup, resulting in oxidative-stress-induced cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPAC-dependent activation of RAF-MEK-ERK signaling as a resistance mechanism to YAP/TAZ inhibition. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms a positive correlation of a YAP/TAZ signature with glycolysis and inverse correlations with oxidative phosphorylation and lysosomal gene expression, supporting the clinical relevance of our findings.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Neurofibromina 2/deficiência , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Glicólise , Xenoenxertos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos SCID , Neurofibromatose 2/genética , Neurofibromatose 2/metabolismo , Neurofibromatose 2/patologia , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Fosforilação Oxidativa , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética
3.
Proc Natl Acad Sci U S A ; 116(15): 7363-7370, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30918126

RESUMO

Coordination of growth and genomic stability is critical for normal cell physiology. Although the E3 ubiquitin ligase BRCA1 is a key player in maintenance of genomic stability, its role in growth signaling remains elusive. Here, we show that BRCA1 facilitates stabilization of YAP1 protein and turning "off" the Hippo pathway through ubiquitination of NF2. In BRCA1-deficient cells Hippo pathway is "turned On." Phosphorylation of YAP1 is crucial for this signaling process because a YAP1 mutant harboring alanine substitutions (Mt-YAP5SA) in LATS1 kinase recognition sites not only resists degradation but also rescues YAP1 transcriptional activity in BRCA1-deficient cells. Furthermore, an ectopic expression of the active Mt-YAP5SA, but not inactive Mt-YAP6SA, promotes EGF-independent proliferation and tumorigenesis in BRCA1-/- mammary epithelial cells. These findings establish an important role of BRCA1 in regulating stability of YAP1 protein that correlates positively with cell proliferation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Neurofibromina 2/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteínas Adaptadoras de Transdução de Sinal/genética , Substituição de Aminoácidos , Proteína BRCA1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Células HEK293 , Humanos , Mutação de Sentido Incorreto , Neurofibromina 2/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética
5.
Oncol Rep ; 41(4): 2103-2116, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816526

RESUMO

Inactivation of the tumor suppressor protein Merlin leads to the development of benign nervous system tumors in neurofibromatosis type2 (NF2). Documented causes of Merlin inactivation include deleterious mutations in the encoding neurofibromin2 gene (NF2) and aberrant Merlin phosphorylation leading to proteasomal degradation. Rare somatic NF2 mutations have also been detected in common human malignancies not associated with NF2, including colorectal and lung cancer. Furthermore, tumors without NF2 mutations and with unaltered NF2 transcript levels, but with low Merlin expression, have been reported. The present study demonstrated that NF2 is also regulated by microRNAs (miRNAs) through direct interaction with evolutionarily conserved miRNA response elements (MREs) within its 3'­untranslated region (3'UTR). Dual­Luciferase assays in human colorectal carcinoma (HCT116) and lung adenocarcinoma (A549) cells revealed downregulation of NF2 by miR­92a­3p via its wild­type 3'UTR, but not NF2­3'UTR with mutated miR­92a­3p MRE. HCT116 cells overexpressing miR­92a­3p exhibited significant downregulation of endogenous NF2 mRNA and protein levels, which was rescued by co­transfection of a target protector oligonucleotide specific for the miR­92a­3p binding site within NF2­3'UTR. miR­92a­3p overexpression in HCT116 and A549 cells promoted migration, proliferation and resistance to apoptosis, as well as altered F­actin organization compared with controls. Knockdown of NF2 by siRNA phenocopied the oncogenic effects of miR­92a overexpression on HCT116 and A549 cells. Collectively, the findings of the present study provide functional proof of the unappreciated role of miRNAs in NF2 regulation and tumor progression, leading to enhanced oncogenicity.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Neurofibromina 2/genética , Regiões 3' não Traduzidas/genética , Células A549 , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação para Baixo , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Neurofibromina 2/metabolismo , RNA Interferente Pequeno/metabolismo
6.
Nat Protoc ; 14(2): 541-555, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30617350

RESUMO

Neurofibromatosis type II (NF2) is a disease that lacks effective therapies. NF2 is characterized by bilateral vestibular schwannomas (VSs) that cause progressive and debilitating hearing loss, leading to social isolation and increased rates of depression. A major limitation in NF2 basic and translational research is the lack of animal models that allow the full spectrum of research into the biology and molecular mechanisms of NF2 tumor progression, as well as the effects on neurological function. In this protocol, we describe how to inject schwannoma cells into the mouse brain cerebellopontine angle (CPA) region. We also describe how to apply state-of-the-art intravital imaging and hearing assessment techniques to study tumor growth and hearing loss. In addition, ataxia, angiogenesis, and tumor-stroma interaction assays can be applied, and the model can be used to test the efficacy of novel therapeutic approaches. By studying the disease from every angle, this model offers the potential to unravel the basic biological underpinnings of NF2 and to develop novel therapeutics to control this devastating disease. Our protocol can be adapted to study other diseases within the CPA, including meningiomas, lipomas, vascular malformations, hemangiomas, epidermoid cysts, cerebellar astrocytomas, and metastatic lesions. The entire surgical procedure takes ~45 min per mouse and allows for subsequent longitudinal imaging, as well as neurological and hearing assessment, for up to 2 months.


Assuntos
Ângulo Cerebelopontino/patologia , Diagnóstico por Imagem/métodos , Modelos Animais de Doenças , Perda Auditiva/patologia , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Animais , Linhagem Celular Tumoral , Ângulo Cerebelopontino/metabolismo , Ângulo Cerebelopontino/cirurgia , Expressão Gênica , Genes Reporter , Audição/fisiologia , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Testes Auditivos , Humanos , Injeções Intraventriculares , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Knockout , Neurofibromatose 2/genética , Neurofibromatose 2/fisiopatologia , Neurofibromina 2/deficiência , Neurofibromina 2/genética , Neuroma Acústico/genética , Neuroma Acústico/fisiopatologia , Técnicas Estereotáxicas
7.
Fam Cancer ; 18(1): 97-100, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29761250

RESUMO

Neurofibromatosis type 2 (NF2) is associated with the development of several types of benign nervous system tumours, while malignancies are rare. We report a 22-year-old man who presented with retroperitoneal and spinal high-grade sarcomas with epithelial features. Samples showed a mixed epithelioid and spindled cell content with little associated matrix and inconclusive immunochemistry. Genetic analysis of a schwannoma and matched blood samples demonstrated a constitutional de novo substitution at the splice donor site of intron 8 of the NF2 gene and aa acquired large deletion of the entire NF2 gene as a second hit, with some loss of SMARCB1. The sarcoma also showed evidence of loss of SMARCB1 and NF2 with loss of INI1 staining. Unfortunately the mass was unresectable and the patient died 6 months after diagnosis. This malignancy was most consistent with SMARCB1-deficient epithelioid malignant peripheral nerve sheath tumour, although a significant differential was proximal-type epithelial sarcoma. Each differential has previously been reported only once with NF2. This demonstrates an extremely rare potential complication of the condition.


Assuntos
Neurofibromatose 2/complicações , Neoplasias Retroperitoneais/diagnóstico , Sarcoma/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diagnóstico Tardio , Diagnóstico Diferencial , Doxorrubicina/uso terapêutico , Evolução Fatal , Humanos , Masculino , Gradação de Tumores , Neurofibromatose 2/genética , Neurofibromina 2/genética , Cuidados Paliativos/métodos , Neoplasias Retroperitoneais/tratamento farmacológico , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/patologia , Proteína SMARCB1/genética , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/patologia , Sorafenibe/uso terapêutico , Neoplasias da Coluna Vertebral/tratamento farmacológico , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/patologia , Adulto Jovem
8.
Hum Mol Genet ; 28(4): 572-583, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30335132

RESUMO

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.


Assuntos
Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Comunicação Autócrina/genética , Carcinogênese/genética , Caspase 1/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Humanos , Camundongos , Terapia de Alvo Molecular , NF-kappa B/genética , Neurilemoma/complicações , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/complicações , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas c-met/genética , Células de Schwann , Transdução de Sinais/genética
9.
Hum Pathol ; 83: 204-211, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29944970

RESUMO

Ovarian ependymomas are rare glial neoplasms that typically occur in women on their third to fourth decades of life. They are histologically similar to ependymomas of the central nervous system but may have a broader immunophenotype. We describe a 27-year-old woman who presented to the emergency department with a 3-week history of cough and shortness of breath. Further workup disclosed a left pelvic mass and extensive intra-abdominal metastases. Pathology revealed sheets of monomorphic cells within a fibrillary stroma, papillary projections, true ependymal rosettes, and pseudorosettes consistent with an ependymoma of ovarian origin. Next-generation sequencing showed ATRX and NF2 copy number losses. Fluorescence in situ hybridization for EWSR1 demonstrated monosomy of 22q in greater than 90% of cells. These molecular alterations have not been previously reported in ovarian or extra-central nervous system ependymomas.


Assuntos
Ependimoma/genética , Neurofibromina 2/genética , Neoplasias Ovarianas/genética , Proteína Nuclear Ligada ao X/genética , Adulto , Ependimoma/patologia , Feminino , Dosagem de Genes , Humanos , Neoplasias Ovarianas/patologia
10.
Cancer Sci ; 110(1): 180-193, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30417500

RESUMO

Malignant pleural mesothelioma (MPM), a highly refractory tumor, is currently incurable due to the lack of an early diagnosis method and medication, both of which are urgently needed to improve the survival and/or quality of life of patients. NF2 is a tumor suppressor gene and is frequently mutated in MPM. Using a CRISPR/Cas9 system, we generated an NF2-knockout human mesothelial cell line, MeT-5A (NF2-KO). In NF2-KO cell clones, cell growth, clonogenic activity, migration activity, and invasion activity significantly increased compared with those in NF2-WT cell clones. Complementary DNA microarray analysis clearly revealed the differences in global gene expression profile between NF2-WT and NF2-KO cell clones. Quantitative PCR analysis and western blot analysis showed that the upregulation of fibroblast growth factor receptor 2 (FGFR2) was concomitant with the increases in phosphorylation levels of JNK, c-Jun, and retinoblastoma (Rb) in NF2-KO cell clones. These increases were all abrogated by the exogenous expression of NF2 in the NF2-KO clone. In addition, the disruption of FGFR2 in the NF2-KO cell clone suppressed cell proliferation as well as the phosphorylation levels of JNK, c-Jun, and Rb. Notably, FGFR2 was found to be highly expressed in NF2-negative human mesothelioma tissues (11/12 cases, 91.7%) but less expressed in NF2-positive tissues. Collectively, these findings suggest that NF2 deficiency might play a role in the tumorigenesis of human mesothelium through mediating FGFR2 expression; FGFR2 would be a candidate molecule to develop therapeutic and diagnostic strategies for targeting MPM with NF2 loss.


Assuntos
Sistemas CRISPR-Cas , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neurofibromina 2/genética , Neoplasias Pleurais/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/metabolismo , Mesotelioma/patologia , Pessoa de Meia-Idade , Neurofibromina 2/metabolismo , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia , Homologia de Sequência do Ácido Nucleico , Adulto Jovem
12.
Dev Biol ; 442(2): 301-314, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30118662

RESUMO

Disruption of endometrial gland formation or function can cause female infertility. Formation of endometrial glands via tubulogenesis of luminal epithelial cells requires the establishment and maintenance of cell polarity and cell adhesion. The FERM domain-containing protein Merlin coordinates epithelial cell polarity and cell adhesion and is critical for epithelial tissue function in the skin and kidney. We now demonstrate a requirement for Merlin in endometrial gland development. Conditional deletion of Merlin in the endometrium results in female infertility caused by the absence of gland formation. Interestingly, we observed glandular epithelial markers within discrete groups of cells in the Merlin-deficient luminal epithelium. Wnt signaling, a pathway necessary for endometrial gland development is maintained in Merlin-deficient endometrium, suggesting the glandular fate program is active. Instead, we observe increased levels of apical actin and markers indicative of high membrane tension on the basal surface of the Merlin-deficient luminal epithelium. These findings suggest that the structural integrity of the luminal epithelium during gland formation is required for appropriate endometrial tubulogenesis and tissue function. Moreover, our work implicates Merlin-dependent regulation of mechanical tension in the proper formation of endometrial gland architecture and function.


Assuntos
Endométrio/crescimento & desenvolvimento , Neurofibromina 2/fisiologia , Animais , Adesão Celular/fisiologia , Polaridade Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Endométrio/citologia , Endométrio/metabolismo , Endométrio/patologia , Células Epiteliais/metabolismo , Feminino , Hibridização In Situ , Infertilidade Feminina , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese/fisiologia , Neurofibromina 2/deficiência , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia
13.
Genes Dev ; 32(17-18): 1201-1214, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30143526

RESUMO

The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availability. We show that merlin deficiency primes the membrane:cytoskeleton interface for epidermal growth factor (EGF)-induced macropinocytosis via a mechanism involving increased cortical ezrin, altered actomyosin, and stabilized cholesterol-rich membranes. These changes profoundly alter EGF receptor (EGFR) trafficking in merlin-deficient cells, favoring increased membrane levels of its heterodimerization partner, ErbB2; clathrin-independent internalization; and recycling. Our work suggests that, unlike Ras transformed cells, merlin-deficient cells do not depend on macropinocytic protein scavenging and instead exploit macropinocytosis for receptor recycling. Finally, we provide evidence that the macropinocytic proficiency of NF2-deficient cells can be used for therapeutic uptake. This work provides new insight into fundamental mechanisms of macropinocytic uptake and processing and suggests new ways to interfere with or exploit macropinocytosis in NF2 mutant and other tumors.


Assuntos
Membrana Celular/metabolismo , Fator de Crescimento Epidérmico/fisiologia , Receptores ErbB/metabolismo , Neurofibromina 2/fisiologia , Pinocitose , Actomiosina/metabolismo , Animais , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Humanos , Camundongos , Neurofibromina 2/genética , Biossíntese de Proteínas
14.
World Neurosurg ; 118: e906-e917, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30031196

RESUMO

BACKGROUND: Although intracranial and spinal ependymomas are histopathologically similar, the molecular landscape is heterogeneous. An urgent need exists to identify differences in the genomic profiles to tailor treatment strategies. In the present study, we delineated differential gene expression patterns between intracranial and spinal ependymomas. METHODS: We searched the Gene Expression Omnibus database using the term "ependymoma" and analyzed the raw gene expression profiles of 292 ependymomas (31 spinal and 261 intracranial). The gene expression data were analyzed to find differentially expressed genes (DEGs) between 2 regions. The fold change (FC) and false discovery rate (FDR) were used to assess DEGs after gene integration (|log2FC|>2; FDR P < 0.01). Enrichment and pathway analysis was also performed. RESULTS: A total of 201 genes (105 upregulated and 96 downregulated) were significant DEGs in the data sets. The underexpression of NF2 in spinal ependymomas was statistically significant (FDR P = 7.91 × 10-9). However, the FC of NF2 did not exceed the cutoff value (log2FC, -1.2). The top 5 ranked upregulated genes were ARX, HOXC6, HOXA9, HOXA5, and HOXA3, which indicated that spinal ependymomas frequently demonstrate overexpression of HOX family genes, which play fundamental roles in specifying anterior/posterior body patterning. Moreover, the gene ontology enrichment analysis specified "anterior/posterior pattern specification" and "neuron migration" in spinal and intracranial ependymomas, respectively. CONCLUSIONS: The most substantial magnitude of DEGs in ependymoma might be HOX genes. However, whether the differential expression of these genes is the cause or consequence of the disease remains to be elucidated in a larger prospective study.


Assuntos
Neoplasias Encefálicas/genética , Bases de Dados Genéticas , Ependimoma/genética , Regulação Neoplásica da Expressão Gênica , Neurofibromina 2/genética , Neoplasias da Medula Espinal/genética , Neoplasias Encefálicas/epidemiologia , Ependimoma/epidemiologia , Genes Homeobox/fisiologia , Humanos , Neurofibromina 2/biossíntese , Estudos Prospectivos , Neoplasias da Medula Espinal/epidemiologia
15.
Carcinogenesis ; 39(9): 1165-1175, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-29893810

RESUMO

The NF2 gene encodes the tumor and metastasis suppressor protein Merlin. Merlin exerts its tumor suppressive role by inhibiting proliferation and inducing contact-growth inhibition and apoptosis. In the current investigation, we determined that loss of Merlin in breast cancer tissues is concordant with the loss of the inhibitory SMAD, SMAD7, of the TGF-ß pathway. This was reflected as dysregulated activation of TGF-ß signaling that co-operatively engaged with effectors of the Hippo pathway (YAP/TAZ/TEAD). As a consequence, the loss of Merlin in breast cancer resulted in a significant metabolic and bioenergetic adaptation of cells characterized by increased aerobic glycolysis and decreased oxygen consumption. Mechanistically, we determined that the co-operative activity of the Hippo and TGF-ß transcription effectors caused upregulation of the long non-coding RNA Urothelial Cancer-Associated 1 (UCA1) that disengaged Merlin's check on STAT3 activity. The consequent upregulation of Hexokinase 2 (HK2) enabled a metabolic shift towards aerobic glycolysis. In fact, Merlin deficiency engendered cellular dependence on this metabolic adaptation, endorsing a critical role for Merlin in regulating cellular metabolism. This is the first report of Merlin functioning as a molecular restraint on cellular metabolism. Thus, breast cancer patients whose tumors demonstrate concordant loss of Merlin and SMAD7 may benefit from an approach of incorporating STAT3 inhibitors.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Glicólise/genética , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/genética , Proteína Smad7/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Inibição de Contato/genética , Genes Supressores de Tumor , Hexoquinase/biossíntese , Humanos , Células MCF-7 , Neurofibromina 2/deficiência , Consumo de Oxigênio/genética , RNA Longo não Codificante/biossíntese , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
16.
Neurosurg Focus ; 44(6): E10, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29852774

RESUMO

Meningiomas are among the most common intracranial pathological conditions, accounting for 36% of intracranial lesions treated by neurosurgeons. Although the majority of these lesions are benign, the classical categorization of tumors by histological type or World Health Organization (WHO) grade has not fully captured the potential for meningioma progression and recurrence. Many targeted treatments have failed to generate a long-lasting effect on these tumors. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor 4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least 6 distinct mutational classes of meningiomas. In addition, 6 methylation classes of meningioma have been appreciated, enabling improved prediction of prognosis compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin. However, despite these exciting findings, the clinical relevance of these findings remains elusive. The authors review the key findings from recent genomic studies in meningiomas, specifically focusing on how these findings relate to clinical insights for the practicing neurosurgeon.


Assuntos
Genômica/métodos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/cirurgia , Meningioma/genética , Meningioma/cirurgia , Neurocirurgiões/educação , Biomarcadores Tumorais/genética , Humanos , Mutação/genética , Neurofibromina 2/genética , Neurocirurgiões/tendências , Receptor Smoothened/genética
17.
PLoS One ; 13(6): e0197350, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29897904

RESUMO

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.


Assuntos
Neoplasias Meníngeas/genética , Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/patologia , Camundongos , Morfolinas/farmacologia , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Panobinostat/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Biologia de Sistemas , Transcriptoma/genética
18.
J Neurol Neurosurg Psychiatry ; 89(11): 1215-1219, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29909380

RESUMO

OBJECTIVES: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. METHODS: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. RESULTS: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%-2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). CONCLUSIONS: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.


Assuntos
Neurilemoma/epidemiologia , Neurilemoma/genética , Neurofibromatoses/epidemiologia , Neurofibromatoses/genética , Neurofibromina 2/genética , Proteína SMARCB1/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética , Prevalência , Adulto Jovem
19.
Development ; 145(9)2018 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-29712669

RESUMO

The architecture of individual cells and cell collectives enables functional specification, a prominent example being the formation of epithelial tubes that transport fluid or gas in many organs. The intrahepatic bile ducts (IHBDs) form a tubular network within the liver parenchyma that transports bile to the intestine. Aberrant biliary 'neoductulogenesis' is also a feature of several liver pathologies including tumorigenesis. However, the mechanism of biliary tube morphogenesis in development or disease is not known. Elimination of the neurofibromatosis type 2 protein (NF2; also known as merlin or neurofibromin 2) causes hepatomegaly due to massive biliary neoductulogenesis in the mouse liver. We show that this phenotype reflects unlimited biliary morphogenesis rather than proliferative expansion. Our studies suggest that NF2 normally limits biliary morphogenesis by coordinating lumen expansion and cell architecture. This work provides fundamental insight into how biliary fate and tubulogenesis are coordinated during development and will guide analyses of disease-associated and experimentally induced biliary pathologies.


Assuntos
Ductos Biliares Intra-Hepáticos/embriologia , Proliferação de Células/fisiologia , Neurofibromina 2/metabolismo , Organogênese/fisiologia , Animais , Ductos Biliares Intra-Hepáticos/patologia , Deleção de Genes , Hepatomegalia/embriologia , Hepatomegalia/genética , Hepatomegalia/patologia , Camundongos , Camundongos Knockout , Neurofibromina 2/genética
20.
Cancer Commun (Lond) ; 38(1): 16, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29764516

RESUMO

BACKGROUND: Extracranial metastasis (ENM) of meningiomas is extremely rare, and typically occurs several years after a primary tumor is diagnosed. However, the genetic changes underlying ENM events have not yet been investigated. CASE PRESENTATION: A 58-year-old male patient was sent to the emergency room of our hospital because of a sudden fall. Magnetic resonance imaging detected a mass at the right frontal sagittal sinus. He underwent tumor resection and recovered well, but post-operative computed tomography revealed three lumps on the right side of his chest. Thoracic surgery was performed to remove two of the lumps. Pathological findings revealed that the brain and lung tumors were grade I meningiomas. The patient received no additional radiation or chemotherapy post-surgery, and there was no sign of tumor recurrence in the brain or progression of the remaining lump in the chest 1 year after surgery. We performed whole exome sequencing of the patient's blood, primary brain tumor, and lung metastatic tumor tissues to identify somatic genetic alterations that had occurred during ENM. This revealed that a frameshift deletion of the neurofibromin 2 gene likely drove formation of the meningioma. Surprisingly, we found that the brain tumor was relatively homogeneous and contained only one dominant clone; both the pulmonary metastasis and the original brain tumor were derived from the same clone, and no obvious additional driver mutations were detected in the metastatic tumor. CONCLUSION: Although ENM of meningiomas is very rare, brain tumor cells appear to be more adaptable to tissue microenvironments outside of the central nervous system than was commonly thought.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Mutação , Neurofibromina 2/genética , Humanos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Masculino , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/cirurgia , Meningioma/patologia , Meningioma/cirurgia , Sequenciamento Completo do Exoma
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