Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Cell Rep ; 42(5): 112472, 2023 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-37149862

RESUMEN

Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Células-Madre Neurales , Animales , Ratones , Glioblastoma/genética , Glioblastoma/patología , Diferenciación Celular , Microambiente Tumoral , Células-Madre Neurales/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología
2.
Dev Cell ; 58(10): 836-846.e6, 2023 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-37084728

RESUMEN

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.


Asunto(s)
Glioblastoma , Células-Madre Neurales , Ratones , Animales , Proteína p53 Supresora de Tumor , PPAR alfa , Dieta , Mutación
4.
Nat Commun ; 12(1): 2594, 2021 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-33972529

RESUMEN

Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.


Asunto(s)
Células Madre Adultas/metabolismo , Ventrículos Laterales/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Células Madre Adultas/citología , Células Madre Adultas/efectos de los fármacos , Animales , Proteína Morfogenética Ósea 4/farmacología , Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/genética , Proteínas de Unión al ADN/metabolismo , Receptores ErbB/farmacología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Ontología de Genes , Inmunohistoquímica , Interferones/farmacología , Ventrículos Laterales/citología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Glicoproteínas de Membrana/genética , Ratones , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Proteómica , RNA-Seq , Regeneración/efectos de los fármacos , Tetraspanina 29/metabolismo , Regulación hacia Arriba
5.
Nat Commun ; 12(1): 2184, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846316

RESUMEN

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.


Asunto(s)
Neoplasias Encefálicas/patología , Diferenciación Celular , Glioblastoma/patología , Sustancia Blanca/patología , Animales , Neoplasias Encefálicas/ultraestructura , Linaje de la Célula , Proliferación Celular , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/ultraestructura , Ratones Endogámicos NOD , Ratones SCID , Vaina de Mielina/metabolismo , Oligodendroglía/patología , Factores de Transcripción SOXE/metabolismo , Transcriptoma/genética , Regulación hacia Arriba/genética
6.
Neuron ; 96(1): 98-114.e7, 2017 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-28957681

RESUMEN

Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFß signaling. TGFß promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals. VIDEO ABSTRACT.


Asunto(s)
Diferenciación Celular , Microambiente Celular/fisiología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Regeneración Nerviosa/fisiología , Traumatismos de los Nervios Periféricos/fisiopatología , Células de Schwann/citología , Células de Schwann/fisiología , Animales , Cadherinas/fisiología , Movimiento Celular/fisiología , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Transgénicos , Traumatismos de los Nervios Periféricos/patología , Cultivo Primario de Células , Ratas , Ratas Transgénicas , Receptores de la Familia Eph/fisiología , Nervio Ciático/lesiones , Nervio Ciático/fisiología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/fisiología
7.
Elife ; 52016 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-27350048

RESUMEN

Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM.


Asunto(s)
Movimiento Celular , Proliferación Celular , Efrina-B2/metabolismo , Glioblastoma/patología , Células Madre Neoplásicas/fisiología , Animales , Xenoinjertos , Humanos , Microscopía Intravital , Ratones
8.
Development ; 132(11): 2513-20, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15857911

RESUMEN

The anterior visceral endoderm (AVE) is an extra-embryonic tissue required for specifying anterior pattern in the mouse embryo. The AVE is induced at the distal tip of the 5.5 dpc embryo and then migrates to the prospective anterior, where it imparts anterior identity upon the underlying epiblast (the tissue that gives rise to the embryo proper). Little is known about how the AVE is induced and what directs its migration. In this paper, we describe an essential role for another extra-embryonic tissue, the extra-embryonic ectoderm (ExE), in patterning the AVE and epiblast. Removal of the ExE in pre-gastrulation embryos leads to ectopic AVE formation, to a failure of AVE cell migration and to the assumption by the entire epiblast of an anterior identity. Ectopic transplantation of ExE cells inhibits AVE formation and leads to an expansion of the posterior epiblast marker T. These results demonstrate that the ExE restricts the induction of the AVE to the distal tip of the mouse embryo and is required to initiate the migration of these cells to the prospective anterior. Together, these data reveal a novel role for the ExE in the specification of the anteroposterior axis of the mouse embryo.


Asunto(s)
Tipificación del Cuerpo/fisiología , Movimiento Celular/fisiología , Ectodermo/fisiología , Inducción Embrionaria/fisiología , Endodermo/fisiología , Ratones/embriología , Animales , Proteínas Fluorescentes Verdes , Hibridación in Situ , Ratones Endogámicos , Micromanipulación
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...