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1.
Cell ; 187(17): 4733-4750.e26, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-38971152

RESUMEN

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.


Asunto(s)
Meduloblastoma , Células Madre Neoplásicas , Humanos , Meduloblastoma/patología , Meduloblastoma/metabolismo , Animales , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Ratones , Rombencéfalo/metabolismo , Rombencéfalo/embriología , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Células Endoteliales/metabolismo , Nicho de Células Madre , Células Madre/metabolismo , Técnicas de Cocultivo , Estructuras Embrionarias , Metencéfalo/embriología
2.
Cell ; 181(6): 1329-1345.e24, 2020 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-32445698

RESUMEN

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.


Asunto(s)
Ependimoma/genética , Ependimoma/metabolismo , Epigenoma/genética , Neoplasias Infratentoriales/genética , Neoplasias Infratentoriales/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular , Proliferación Celular/genética , Metilación de ADN/genética , Epigenómica/métodos , Histonas/genética , Histonas/metabolismo , Humanos , Lactante , Lisina/genética , Lisina/metabolismo , Masculino , Ratones Endogámicos C57BL , Mutación/genética
4.
Nat Med ; 26(5): 720-731, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32341580

RESUMEN

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.


Asunto(s)
Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/administración & dosificación , Líquido Cefalorraquídeo/efectos de los fármacos , Ependimoma/terapia , Inmunoterapia Adoptiva/métodos , Meduloblastoma/terapia , Animales , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Cerebelosas/líquido cefalorraquídeo , Neoplasias Cerebelosas/inmunología , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/terapia , Líquido Cefalorraquídeo/inmunología , Niño , Preescolar , Sistemas de Liberación de Medicamentos/métodos , Ependimoma/líquido cefalorraquídeo , Ependimoma/inmunología , Ependimoma/patología , Femenino , Células HEK293 , Humanos , Lactante , Inyecciones Intraventriculares , Masculino , Meduloblastoma/líquido cefalorraquídeo , Meduloblastoma/inmunología , Meduloblastoma/patología , Ratones , Metástasis de la Neoplasia , Receptores Quiméricos de Antígenos/administración & dosificación , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplante , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
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