Exosome-Filopodia Interactions

外泌体是晚期内体衍生的小的细胞外囊泡，其携带生物活性物质， 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分泌外泌体。 此外，初步报告表明，分泌的外泌体对 几个生理过程，包括入侵和运动，干细胞的命运， 血管生成然而，外泌体对细胞的特异性生物学效应很差， 明白我们最近发现了一种侵入性的肌动蛋白基突起，称为侵入性伪足 作为含有外泌体的多泡内体（MVE）的特异性对接位点， 显示外泌体分泌控制侵入伪足的生物发生和活性。我们 进一步的研究发现了外泌体在调节细胞增殖中的基本作用。 形成额外的相关肌动蛋白为基础的运动结构：粘连，和丝状伪足。 外泌体似乎对丝状伪足有特别强的作用， 肌动蛋白为基础的突起是重要的方向感测，细胞极性，细胞 运动和细胞相互作用。因此，我们提出了一个中心假设， 外泌体的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健的丝状伪足，而丝状伪足控制着关键的细胞行为。 我们将确定外泌体分泌与细胞凋亡之间的时间和功能关系。 丝状伪足形成我们将确定控制丝状伪足的分子外泌体货物 形成和成熟，并决定其作用机制。最后我们 将决定外泌体在调节复杂的丝状伪足依赖性 过程，包括突触形成和定向迁移在体外和体内。

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 in 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.