title: Induction and transport of Wnt 5a during macrophage-induced malignant invasion is mediated by two types of extracellular vesicles.
abstract: Recently, we have shown that macrophage (MΦ)-induced invasion of breast cancer cells requires upregulation of Wnt 5a in MΦ leading to activation of β-Catenin-independent Wnt signaling in the tumor cells. However, it remained unclear, how malignant cells induce Wnt 5a in MΦ and how it is transferred back to the cancer cells. Here we identify two types of extracellular particles as essential for this intercellular interaction in both directions. Plasma membrane-derived microvesicles (MV) as well as exosomes from breast cancer cells, although biologically distinct populations, both induce Wnt 5a in MΦ. In contrast, the particle-free supernatant and vesicles from benign cells, such as platelets, have no such effect. Induction is antagonized by the Wnt inhibitor Dickkopf-1. Subsequently, Wnt 5a is shuttled via responding MΦ-MV and exosomes to the tumor cells enhancing their invasion. Wnt 5a export on both vesicle fractions depends at least partially on the cargo protein Evenness interrupted (Evi). Its knockdown leads to Wnt 5a depletion of both particle populations and reduced vesicle-mediated invasion. In conclusion, MV and exosomes are critical for MΦ-induced invasion of cancer cells since they are responsible for upregulation of MΦ-Wnt 5a as well as for its delivery to the recipient cells via a reciprocal loop. Although of different biogenesis, both populations share common features regarding function and Evi-dependent secretion of non-canonical Wnts.
authors.affiliation: Department of Hematology/Oncology, University Medicine, Göttingen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Menck
authors.forename: Florian
authors.initials: F
authors.lastname: Klemm
authors.forename: Julia Christina
authors.initials: JC
authors.lastname: Gross
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
authors.forename: Dirk
authors.initials: D
authors.lastname: Wenzel
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism; D051153:Wnt Proteins / Q000096:biosynthesis / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein