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1.
EMBO J ; 39(1): e102030, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31774199

RESUMEN

Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-κB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impairs autophagic flux, and culminates in lysosomal-mediated cell death, concomitantly with mTOR inactivation and dispersion from endo-lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Endosomas/patología , Glioma/patología , Homeostasis , Lisosomas/patología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Células Madre Neoplásicas/patología , Anciano , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Endosomas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/metabolismo , Humanos , Activación de Linfocitos , Lisosomas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Células Madre Neoplásicas/metabolismo , Proteolisis , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Sci Rep ; 11(1): 22792, 2021 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-34815502

RESUMEN

Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/patología , Vesículas Extracelulares/metabolismo , Glioblastoma/patología , Proteoma/metabolismo , Microambiente Tumoral/inmunología , Factor de von Willebrand/metabolismo , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Glioblastoma/sangre , Glioblastoma/inmunología , Glioblastoma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Proteoma/análisis
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