RESUMEN
Infiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM). We show here that GBM cells upregulate guidance receptor Plexin-B2 to gain invasiveness. Deletion of Plexin-B2 in GBM stem cells limited tumor spread and shifted invasion paths from axon fiber tracts to perivascular routes. On a cellular level, Plexin-B2 adjusts cell adhesiveness, migratory responses to different matrix stiffness, and actomyosin dynamics, thus empowering GBM cells to leave stiff tumor bulk and infiltrate softer brain parenchyma. Correspondingly, gene signatures affected by Plexin-B2 were associated with locomotor regulation, matrix interactions, and cellular biomechanics. On a molecular level, the intracellular Ras-GAP domain contributed to Plexin-B2 function, while the signaling relationship with downstream effectors Rap1/2 appeared variable between GBM stem cell lines, reflecting intertumoral heterogeneity. Our studies establish Plexin-B2 as a modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Movimiento Celular , Glioblastoma/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Fenómenos Biomecánicos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Uniones Célula-Matriz/genética , Uniones Célula-Matriz/metabolismo , Uniones Célula-Matriz/patología , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/patología , Humanos , Masculino , Ratones Endogámicos ICR , Ratones SCID , Invasividad Neoplásica , Proteínas del Tejido Nervioso/genética , Semaforinas/genética , Semaforinas/metabolismo , Complejo Shelterina , Transducción de Señal , Proteínas de Unión a Telómeros/genética , Proteínas de Unión a Telómeros/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcriptoma , Proteínas Señalizadoras YAP , Proteínas de Unión al GTP rap/genética , Proteínas de Unión al GTP rap/metabolismoRESUMEN
Pluripotent stem cells (PSCs) represent an exciting cell source for tissue engineering and regenerative medicine due to their self-renewal and differentiation capacities. The majority of current PSC protocols rely on 2D cultures and soluble factors to guide differentiation; however, many other environmental signals are beginning to be explored using biomaterial platforms. Biomaterials offer new opportunities to engineer the stem cell niches and 3D environments for exploring biophysical and immobilized signaling cues to further our control over stem cell fate. Here, we review the biomaterial platforms that have been engineered to control PSC fate. We explore how altering immobilized biochemical cues and biophysical cues such as dimensionality, stiffness, and topography can enhance our control over stem cell fates. Finally, we highlight biomaterial culture systems that assist in the translation of PSC technologies for clinical applications.
