Exosome-Filopodia Interactions

 描述（由申请人提供）：外泌体是小的晚期内体衍生的细胞外囊泡，其携带生物活性蛋白和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分泌外泌体。此外，初步报告表明，分泌的外泌体对几种生理过程有重要贡献，包括侵入和运动、干细胞命运和细胞增殖。 血管生成然而，外泌体对细胞的特定生物学效应知之甚少。我们最近确定了侵入性肌动蛋白为基础的突起称为invadopodia作为特定的对接站点外泌体含有多泡内体（MVE），并表明外泌体分泌控制invadopodia的生物发生和活动。我们的进一步研究揭示了外泌体在调节其他相关肌动蛋白为基础的运动结构的形成中的基本作用：粘连和丝状伪足。外泌体似乎对丝状伪足具有特别有效的作用，丝状伪足是基于肌动蛋白的粘附性突起，对于方向感测、细胞极性、细胞运动和细胞相互作用很重要。因此，我们提出了一个中心假设，即外泌体的一个关键功能是促进丝状伪足的形成，从而控制局部细胞行为。我们将在癌细胞和神经元中检验这一假设，因为这些细胞表现出强大的丝状伪足，丝状伪足控制关键的细胞行为。我们将确定外泌体分泌和丝状伪足形成之间的时间和功能关系。我们将确定控制丝状伪足形成和成熟的分子外泌体货物，并确定它们的作用机制。最后，我们将确定外泌体在调节复杂的丝状伪足依赖性过程中的作用，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.