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1.
Nature ; 623(7986): 366-374, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37914930

RESUMO

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.


Assuntos
Adaptação Fisiológica , Glioma , Plasticidade Neuronal , Sinapses , Animais , Criança , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proliferação de Células , Progressão da Doença , Glioma/metabolismo , Glioma/patologia , Ácido Glutâmico/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de AMPA/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Microambiente Tumoral , Optogenética
2.
Nature ; 594(7862): 277-282, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34040258

RESUMO

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.


Assuntos
Transformação Celular Neoplásica/genética , Genes da Neurofibromatose 1 , Mutação , Neurofibromina 1/genética , Neurônios/metabolismo , Glioma do Nervo Óptico/genética , Glioma do Nervo Óptico/patologia , Animais , Astrocitoma/genética , Astrocitoma/patologia , Moléculas de Adesão Celular Neuronais/deficiência , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Transformação Celular Neoplásica/efeitos da radiação , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos da radiação , Nervo Óptico/citologia , Nervo Óptico/efeitos da radiação , Estimulação Luminosa , Retina/citologia , Retina/efeitos da radiação
3.
Acta Biomater ; 116: 201-208, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32911104

RESUMO

Brain tumors exhibit vast genotypic and phenotypic diversity depending on patient age and anatomical location. Hydrogels hold great promise as 3D in vitro models for studying brain tumor biology and drug screening, yet previous studies were limited to adult glioblastoma cells, and most studies used immortalized cell lines. Here we report a hydrogel platform that supports the proliferation and invasion of patient-derived brain tumor cell cultures (PDCs) isolated from different patient age groups and anatomical locations. Hydrogel stiffness was tuned by varying poly(ethylene-glycol) concentration. Cell adhesive peptide (CGRDS), hyaluronic acid, and MMP-cleavable crosslinkers were incorporated to facilitate cell adhesion and cell-mediated degradation. Three PDC lines were compared including adult glioblastoma cells (aGBM), pediatric glioblastoma cells (pGBM), and diffuse pontine intrinsic glioma (DIPG). A commonly used immortalized adult glioblastoma cell line U87 was included as a control. PDCs displayed stiffness-dependent behavior, with 40 Pa hydrogel promoting faster tumor proliferation and invasion. Adult GBM cells exhibited faster proliferation than pediatric GBM, and DIPG showed slowest proliferation. These results suggest both patient age and tumor location affects brain tumor behaviors. Adult GBM PDCs also exhibited very different cell proliferation and morphology from U87. The hydrogel reported here can provide a useful tool for future studies to better understand how age and anatomical locations impacts brain tumor progression using 3D in vitro models.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Biomimética , Linhagem Celular Tumoral , Criança , Humanos , Hidrogéis
4.
Nature ; 573(7775): 539-545, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31534222

RESUMO

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.


Assuntos
Encéfalo/fisiopatologia , Sinapses Elétricas/patologia , Fenômenos Eletrofisiológicos , Glioma/fisiopatologia , Animais , Encéfalo/citologia , Membrana Celular/patologia , Proliferação de Células , Junções Comunicantes/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Neurônios/patologia , Optogenética , Potássio/metabolismo , Transmissão Sináptica , Células Tumorais Cultivadas
5.
Cancer Cell ; 31(5): 635-652.e6, 2017 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-28434841

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azepinas/farmacologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Fenilenodiaminas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Transcrição Gênica/efeitos dos fármacos , Triazóis/farmacologia , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/metabolismo , Neoplasias do Tronco Encefálico/patologia , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Panobinostat , Cultura Primária de Células , Interferência de RNA , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase Ativadora de Quinase Dependente de Ciclina
6.
Sci Transl Med ; 9(381)2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28298418

RESUMO

Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.


Assuntos
Anticorpos/uso terapêutico , Antígenos de Diferenciação/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Antígeno CD47/imunologia , Fagocitose , Receptores Imunológicos/metabolismo , Animais , Anticorpos/farmacologia , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Criança , Modelos Animais de Doenças , Humanos , Imunocompetência , Injeções Intraventriculares , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/secundário , Camundongos Endogâmicos C57BL , Modelos Biológicos , Metástase Neoplásica , Fagocitose/efeitos dos fármacos , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nat Med ; 21(6): 555-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25939062

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.


Assuntos
Benzazepinas/administração & dosagem , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma/tratamento farmacológico , Ácidos Hidroxâmicos/administração & dosagem , Indóis/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Glioma/genética , Glioma/patologia , Humanos , Panobinostat , Análise de Sequência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Med ; 20(7): 732-40, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24973920

RESUMO

Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.


Assuntos
Epigênese Genética , Proteínas Hedgehog/genética , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Transcrição Gênica , Animais , Azepinas/farmacologia , Proteínas Hedgehog/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Ligantes , Camundongos , Neoplasias Experimentais/patologia , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Proteína GLI1 em Dedos de Zinco , Proteína Gli2 com Dedos de Zinco
10.
Cancer Cell ; 24(5): 660-72, 2013 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-24183680

RESUMO

Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ∼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias do Tronco Encefálico/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Histonas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Linhagem Celular Tumoral , Criança , Epigênese Genética , Genes Dominantes , Glioblastoma/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Metilação , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Complexo Repressor Polycomb 2/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Fatores de Transcrição , Transcrição Gênica
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