title: The mannose receptor LY75 (DEC205/CD205) modulates cellular phenotype and metastatic potential of ovarian cancer cells.
abstract: The molecular basis of epithelial ovarian cancer (EOC) dissemination is still poorly understood. Previously, we identified the mannose receptor LY75 gene as hypomethylated in high-grade (HG) serous EOC tumors, compared to normal ovarian tissues. LY75 represents endocytic receptor expressed on dendritic cells and so far, has been primarily studied for its role in antigen processing and presentation. Here we demonstrate that LY75 is overexpressed in advanced EOC and that LY75 suppression induces mesenchymal-to-epithelial transition (MET) in EOC cell lines with mesenchymal morphology (SKOV3 and TOV112), accompanied by reduction of their migratory and invasive capacity in vitro and enhanced tumor cell colonization and metastatic growth in vivo. LY75 knockdown in SKOV3 cells also resulted in predominant upregulation of functional pathways implicated in cell proliferation and metabolism, while pathways associated with cell signaling and adhesion, complement activation and immune response were mostly suppressed. Moreover, LY75 suppression had an opposite effect on EOC cell lines with epithelial phenotype (A2780s and OV2008), by directing epithelial-to-mesenchymal transition (EMT) associated with reduced capacity for in vivo EOC cell colonization, as similar/identical signaling pathways were reversely regulated, when compared to mesenchymal LY75 knockdown EOC cells.To our knowledge, this is the first report of a gene displaying such pleiotropic effects in sustaining the cellular phenotype of EOC cells and points to novel functions of this receptor in modulating EOC dissemination. Our data also support previous findings regarding the superior capacity of epithelial cancer cells in metastatic colonization of distant sites, compared to cancer cells with mesenchymal-like morphology.
authors.affiliation: Department of Molecular Medicine, Université Laval, Québec, Canada.|Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.
authors.forename: Adnen
authors.initials: A
authors.lastname: Faddaoui
authors.affiliation: Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bachvarova
authors.affiliation: Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.|Department of Obstetrics and Gynecology, Université Laval, Québec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Plante
authors.affiliation: Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.|Department of Obstetrics and Gynecology, Université Laval, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Gregoire
authors.affiliation: Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.|Department of Obstetrics and Gynecology, Université Laval, Québec, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Renaud
authors.affiliation: Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.|Department of Obstetrics and Gynecology, Université Laval, Québec, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sebastianelli
authors.affiliation: Department of Molecular Medicine, Université Laval, Québec, Canada.|Centre de Recherche du CHU de Québec, CHUL, Québec, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Gobeil
authors.affiliation: Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.
authors.forename: Chantale
authors.initials: C
authors.lastname: Morin
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macdonald
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vanderhyden
authors.affiliation: Department of Molecular Medicine, Université Laval, Québec, Canada.|Centre de Recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.
authors.forename: Dimcho
authors.initials: D
authors.lastname: Bachvarov
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000556:secondary*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000556:secondary*; D010641:Phenotype; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface
keywords: LY75 (DEC205); epithelial ovarian cancer; epithelial-to-mesenchymal transition; intraperitoneal xenografts; shRNA and CRISPR/Cas9