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.
This project is relevant to human health because it investigates basic processes that control cancer invasion and neuron protrusion formation. Therefore, it could identify molecules that control diseases, such as cancer metastasis as well as neurological disorders. Thus, our findings could lead to the development of new therapeutic approaches to treat these disorders.
