title: Exosome secretion is enhanced by invadopodia and drives invasive behavior.
abstract: Unconventional secretion of exosome vesicles from multivesicular endosomes (MVEs) occurs across a broad set of systems and is reported to be upregulated in cancer, where it promotes aggressive behavior. However, regulatory control of exosome secretion is poorly understood. Using cancer cells, we identified specialized invasive actin structures called invadopodia as specific and critical docking and secretion sites for CD63- and Rab27a-positive MVEs. Thus, inhibition of invadopodia formation greatly reduced exosome secretion into conditioned media. Functionally, addition of purified exosomes or inhibition of exosome biogenesis or secretion greatly affected multiple invadopodia life cycle steps, including invadopodia formation, stabilization, and exocytosis of proteinases, indicating a key role for exosome cargoes in promoting invasive activity and providing in situ signaling feedback. Exosome secretion also controlled cellular invasion through three-dimensional matrix. These data identify a synergistic interaction between invadopodia biogenesis and exosome secretion and reveal a fundamental role for exosomes in promoting cancer cell invasiveness.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hoshino
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Kellye C
authors.initials: KC
authors.lastname: Kirkbride
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Costello
authors.affiliation: Department of Microbiology and Immunology, University of Miami Medical School, Miami, FL 33101, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Clark
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Grega-Larson
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Tyska
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: alissa.weaver@vanderbilt.edu.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Weaver
mesh_terms: D000199:Actins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D005089:Exocytosis; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D011554:Pseudopodia / Q000378:metabolism*; D055571:Secretory Pathway; D060149:Tetraspanin 30 / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D000199:Actins; C554586:CD63 protein, human; D060149:Tetraspanin 30; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins