Oncotarget

Research Papers:

The mannose receptor LY75 (DEC205/CD205) modulates cellular phenotype and metastatic potential of ovarian cancer cells

Adnen Faddaoui _, Magdalena Bachvarova, Marie Plante, Jean Gregoire, Marie-Claude Renaud, Alexandra Sebastianelli, Stephane Gobeil, Chantale Morin, Elizabeth Macdonald, Barbara Vanderhyden and Dimcho Bachvarov

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Oncotarget. 2016; 7:14125-14142. https://doi.org/10.18632/oncotarget.7288

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Abstract

Adnen Faddaoui1,2, Magdalena Bachvarova2, Marie Plante2,3, Jean Gregoire2,3, Marie-Claude Renaud2,3, Alexandra Sebastianelli2,3, Stephane Gobeil1,4, Chantale Morin2, Elizabeth Macdonald5, Barbara Vanderhyden5, Dimcho Bachvarov1,2

1Department of Molecular Medicine, Université Laval, Québec, Canada

2Centre de recherche du CHU de Québec, L’Hôtel-Dieu de Québec, Québec, Canada

3Department of Obstetrics and Gynecology, Université Laval, Québec, Canada

4Centre de recherche du CHU de Québec, CHUL, Québec, Canada

5Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

Correspondence to:

Dimcho Bachvarov, e-mail: [email protected]

Keywords: LY75 (DEC205), epithelial ovarian cancer, epithelial-to-mesenchymal transition, intraperitoneal xenografts, shRNA & CRISPR/Cas9

Received: December 28, 2015     Accepted: January 29, 2016     Published: February 9, 2016

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.


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