Role of endosomal sorting in the biogenesis of extracellular vesicles

点击翻译按钮获取中文摘要

During development and adult tissue homeostasis cells integrate intrinsic and extrinsic cues into signals that are shared with the surrounding cell population. These signals can synchronize or desynchronize cellular behavior and coordinate position and fate of individual cells. Morphogens gradients have been intensively investigated for their role in pattern formation. The molecular form of these gradients was long considered to be secreted protein ligands, which activate different signaling pathways on receiving cells. Abberant activation of these signaling pathways leads to the progression of cancer. However, increasing evidence suggests that extracellular vesicles (EVs) are the carriers of such messages. They are a heterogeneous population of membrane particles released into the extracellular space in vitro and in vivo. But how these structures are released from endosomal compartments and how signaling from one cell to another occurs remains elusive. In the proposed project we will study the secretion and signaling of EVs in the context of cell migration in tumor cells. We will focus on the source of EVs and what cellular processes regulated their release. This will be done by analyzing: (1) the dynamics of microvesicles and exosomes release, (2) the composition and regulation of secretory MVBs, (3) exosomal subpopulations by multi-color STED and (4) the mechanism of polarized EVs secretion in cell migration.Specifically, we want to understand endosomal sorting events that influence and regulate EV secretion by using an induced Wnt5A secretion as a model EV cargo sorted into sMVBs and released in an ESCRT-0-dependent manner to deduce how EV signals are decoded in the context of directed cell migration. Altogether, this project will provide a deep insight into cellular communication via EVs. Understanding their biological role in migration will add a new layer to extracellular signaling pathways.In the proposed project we will study the secretion and signaling of EVs in the context of cell migration in tumor cells. We will use single cell assays to mechanistically dissect the spatio-temporal modalities of EV release. Specifically, we want to understand endosomal sorting events that influence and regulate their secretion and investigate the dynamics and biogenesis of subpopulations of EVs. We will focus on the composition of signaling EVs, which pathways they activate and deduce how EV signals are decoded in the context of directed cell migration. Altogether, this project will provide a deep insight into cellular communication via EVs. Understanding their biological role in migration, their transmission and reception will add a new layer to extracellular signaling pathways.