title: Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration.
abstract: Stroma in the tumor microenvironment plays a critical role in cancer progression, but how it promotes metastasis is poorly understood. Exosomes are small vesicles secreted by many cell types and enable a potent mode of intercellular communication. Here, we report that fibroblast-secreted exosomes promote breast cancer cell (BCC) protrusive activity and motility via Wnt-planar cell polarity (PCP) signaling. We show that exosome-stimulated BCC protrusions display mutually exclusive localization of the core PCP complexes, Fzd-Dvl and Vangl-Pk. In orthotopic mouse models of breast cancer, coinjection of BCCs with fibroblasts dramatically enhances metastasis that is dependent on PCP signaling in BCCs and the exosome component, Cd81 in fibroblasts. Moreover, we demonstrate that trafficking in BCCs promotes tethering of autocrine Wnt11 to fibroblast-derived exosomes. This work reveals an intercellular communication pathway whereby fibroblast exosomes mobilize autocrine Wnt-PCP signaling to drive BCC invasive behavior.
authors.affiliation: Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Valbona
authors.initials: V
authors.lastname: Luga
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Viloria-Petit
authors.forename: Abiodun A
authors.initials: AA
authors.lastname: Ogunjimi
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Inanlou
authors.forename: Elaine
authors.initials: E
authors.lastname: Chiu
authors.forename: Marguerite
authors.initials: M
authors.lastname: Buchanan
authors.forename: Abdel Nasser
authors.initials: AN
authors.lastname: Hosein
authors.forename: Mark
authors.initials: M
authors.lastname: Basik
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D060225:Tetraspanin 28; D059016:Tumor Microenvironment; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C554798:CD81 protein, human; D060225:Tetraspanin 28; D051153:Wnt Proteins; C540523:Wnt11 protein, human