Exosome-Filopodia Interactions

 描述(申请人提供)：外体是小的晚期内体衍生的细胞外小泡，携带生物活性蛋白质和RNA分子，并调节细胞行为。最近的数据表明，包括癌细胞和神经元在内的多种细胞都能分泌外切体。此外，初步报告表明，分泌的外切体在几个生理过程中起关键作用，包括侵袭和移动、干细胞命运和 血管生成。然而，外切体对细胞的特定生物学效应却知之甚少。我们最近发现以肌动蛋白为基础的侵袭性突起称为invadodia，是含有外体的多囊内体(MVE)的特定对接位置，并表明外体分泌控制inadodia的生物发生和活动。我们的进一步研究揭示了外体在调节其他相关的基于肌动蛋白的运动结构的形成中的基本作用：粘连和丝状伪足。外切体似乎对丝状伪足有特别强大的影响，丝状伪足是一种基于粘附性肌动蛋白的突起，对定向感知、细胞极性、细胞运动和细胞相互作用都很重要。因此，我们提出了一个中心假设，即外切体的一个关键功能是促进丝状足的形成，从而控制局部细胞行为。我们将在癌细胞和神经元上验证这一假设，因为这些细胞表现出强大的丝状伪足和控制关键细胞行为的丝状伪足。我们将确定外切体分泌和丝足形成之间的时间和功能关系。我们将鉴定控制丝状孢子形成和成熟的分子外切体，并确定它们的作用机制。最后，我们将确定外体在调节复杂的丝足依赖过程中的作用，包括体外和体内的突触形成和定向迁移。

 DESCRIPTION (provided by applicant): Exosomes are small late endosome-derived extracellular vesicles that carry bioactive protein and RNA molecules and modulate cell behavior. Recent data indicate that a wide variety of cells, including cancer cells and neurons, secrete exosomes. Furthermore, preliminary reports indicate that secreted exosomes critically contribute to several physiological processes, including invasion and motility, stem cell fate, and angiogenesis. However, the specific biological effects of exosomes on cells are poorly understood. We recently identified invasive actin-based protrusions called invadopodia as specific docking sites for exosome-containing multivesicular endosomes (MVE) and showed that exosome secretion controls invadopodia biogenesis and activity. Our further investigations have uncovered a fundamental role for exosomes in regulating the formation of additional related actin-based motility structures: adhesions, and filopodia. Exosomes appear to have a particularly potent effect on filopodia, which are adhesive actin-based protrusions that are important for directional sensing, cell polarity, cell movement, and cellular interactions. We therefore propose the central hypothesis that a key function of exosomes is to promote formation of filopodia and thereby control local cellular behaviors. We will test this hypothesis i both cancer cells and neurons because these cells exhibit robust filopodia and filopodia control key cellular behaviors. We will identify the temporal and functional relationship between exosome secretion and filopodia formation. We will identify molecular exosome cargos that control filopodia formation and maturation and determine the mechanisms by which they act. Finally, we will determine the role of exosomes in regulating complex filopodia-dependent processes, including synapse formation and directed migration both in vitro and in vivo.