RESUMEN
Among mammary tumor-infiltrating immune cells, the highest expression of podoplanin (PDPN) is found in a subset of tumor-associated macrophages (TAMs). We hereby demonstrate that PDPN is involved in the attachment of this TAM subset to lymphatic endothelial cells (LECs). Mechanistically, the binding of PDPN to LEC-derived galectin 8 (GAL8) in a glycosylation-dependent manner promotes the activation of pro-migratory integrin ß1. When proximal to lymphatics, PDPN-expressing macrophages (PoEMs) stimulate local matrix remodeling and promote vessel growth and lymphoinvasion. Anti-integrin ß1 blockade, macrophage-specific Pdpn knockout, or GAL8 inhibition impairs TAM adhesion to LECs, restraining lymphangiogenesis and reducing lymphatic cancer spread. In breast cancer patients, association of PoEMs with tumor lymphatic vessels correlates with incidences of lymph node and distant organ metastasis.
Asunto(s)
Neoplasias de la Mama/metabolismo , Ganglios Linfáticos/patología , Linfangiogénesis/genética , Metástasis Linfática/genética , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Células Endoteliales/metabolismo , Matriz Extracelular/metabolismo , Femenino , Humanos , Vasos Linfáticos/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana EdadRESUMEN
GABAergic interneurons mainly originate in the medial ganglionic eminence (MGE) of the embryonic ventral telencephalon (VT) and migrate tangentially to the cortex, guided by membrane-bound and secreted factors. We found that Sip1 (Zfhx1b, Zeb2), a transcription factor enriched in migrating cortical interneurons, is required for their proper differentiation and correct guidance. The majority of Sip1 knockout interneurons fail to migrate to the neocortex and stall in the VT. RNA sequencing reveals that Sip1 knockout interneurons do not acquire a fully mature cortical interneuron identity and contain increased levels of the repulsive receptor Unc5b. Focal electroporation of Unc5b-encoding vectors in the MGE of wild-type brain slices disturbs migration to the neocortex, whereas reducing Unc5b levels in Sip1 knockout slices and brains rescues the migration defect. Our results reveal that Sip1, through tuning of Unc5b levels, is essential for cortical interneuron guidance.
Asunto(s)
Movimiento Celular/fisiología , Corteza Cerebral/crecimiento & desarrollo , Interneuronas/fisiología , Neocórtex/crecimiento & desarrollo , Proteínas del Tejido Nervioso/deficiencia , Receptores de Superficie Celular/deficiencia , Animales , Corteza Cerebral/citología , Técnicas de Inactivación de Genes , Ratones , Ratones Transgénicos , Neocórtex/citología , Proteínas del Tejido Nervioso/genética , Receptores de Netrina , Técnicas de Cultivo de Órganos , Receptores de Superficie Celular/genética , Telencéfalo/citología , Telencéfalo/crecimiento & desarrolloRESUMEN
Signaling by the many ligands of the TGFß family strongly converges towards only five receptor-activated, intracellular Smad proteins, which fall into two classes i.e. Smad2/3 and Smad1/5/8, respectively. These Smads bind to a surprisingly high number of Smad-interacting proteins (SIPs), many of which are transcription factors (TFs) that co-operate in Smad-controlled target gene transcription in a cell type and context specific manner. A combination of functional analyses in vivo as well as in cell cultures and biochemical studies has revealed the enormous versatility of the Smad proteins. Smads and their SIPs regulate diverse molecular and cellular processes and are also directly relevant to development and disease. In this survey, we selected appropriate examples on the BMP-Smads, with emphasis on Smad1 and Smad5, and on a number of SIPs, i.e. the CPSF subunit Smicl, Ttrap (Tdp2) and Sip1 (Zeb2, Zfhx1b) from our own research carried out in three different vertebrate models.