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1.
Nat Genet ; 48(11): 1339-1348, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27723760

RESUMO

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.


Assuntos
Metilação de DNA , Neoplasias da Orelha/genética , Mutação , Neurilemoma/genética , Neoplasias da Coluna Vertebral/genética , Vestíbulo do Labirinto , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Linhagem Celular Tumoral , Análise Mutacional de DNA , DNA de Neoplasias , Exoma , Feminino , Fusão Gênica , Genoma Humano , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Neoplásico , Análise de Sequência de DNA , Análise de Sequência de RNA , Serina Endopeptidases/genética
2.
Oncotarget ; 7(43): 69518-69535, 2016 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-27588472

RESUMO

First-line cancer therapies such as alkylating agents and radiation have limited survival benefits for Glioblastoma (GBM) patients. Current research strongly supports the notion that inhibition of aberrant tumor metabolism holds promise as a therapeutic strategy when used in combination with radiation and chemotherapy. Hexokinase 2 (HK2) has been shown to be a key driver of altered metabolism in GBM, and presents an attractive therapeutic target. To date, no study has fully assessed the therapeutic value of targeting HK2 as a mechanism to sensitize cells to standard therapy, namely in the form of radiation and temozolomide (TMZ). Using cell lines and primary cultures of GBM, we showed that inducible knockdown of HK2 altered tumor metabolism, which could not be recapitulated by HK1 or HK3 loss. HK2 loss diminished both in vivo tumor vasculature as well as growth within orthotopic intracranial xenograft models of GBMs, and the survival benefit was additive with radiation and TMZ. Radio-sensitization following inhibition of HK2 was mediated by increased DNA damage, and could be rescued through constitutive activation of ERK signaling. This study supports HK2 as a potentially effective therapeutic target in GBM.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Hexoquinase/genética , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia , Dano ao DNA , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Células HEK293 , Hexoquinase/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Temozolomida
3.
Arch Immunol Ther Exp (Warsz) ; 61(1): 25-41, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23224339

RESUMO

Glioblastoma (GBM) is the most common and lethal primary brain tumor. Over the past few years tremendous genomic and proteomic characterization along with robust animal models of GBM have provided invaluable data that show that "GBM", although histologically indistinguishable from one another, are comprised of molecularly heterogenous diseases. In addition, robust pre-clinical models and a better understanding of the core pathways disrupted in GBM are providing a renewed optimism for novel strategies targeting these devastating tumors. Here, we summarize a brief history of the disease, our current molecular knowledge, lessons from animal models and emerging concepts of angiogenesis, invasion, and metabolism in GBM that may lend themselves to therapeutic targeting.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Animais , Neoplasias Encefálicas/história , Modelos Animais de Doenças , Glioblastoma/história , História do Século XX , História do Século XXI , Humanos , Terapia de Alvo Molecular/tendências , Invasividade Neoplásica , Proteômica
4.
PLoS One ; 5(5): e10901, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20531938

RESUMO

The mechanism by which an apparently uniform population of cells can generate a heterogeneous population of differentiated derivatives is a fundamental aspect of pluripotent and multipotent stem cell behaviour. One possibility is that the environment and the differentiation cues to which the cells are exposed are not uniform. An alternative, but not mutually exclusive possibility is that the observed heterogeneity arises from the stem cells themselves through the existence of different interconvertible substates that pre-exist before the cells commit to differentiate. We have tested this hypothesis in the case of apparently homogeneous pluripotent human embryonal carcinoma (EC) stem cells, which do not follow a uniform pattern of differentiation when exposed to retinoic acid. Instead, they produce differentiated progeny that include both neuronal and non-neural phenotypes. Our results suggest that pluripotent NTERA2 stem cells oscillate between functionally distinct substates that are primed to select distinct lineages when differentiation is induced.


Assuntos
Compartimento Celular , Diferenciação Celular , Células-Tronco/citologia , Carcinoma Embrionário/patologia , Linhagem da Célula , Células Clonais , Humanos , Modelos Biológicos , Fenótipo
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