Novel Axl-driven signaling pathway and molecular signature characterize high-grade ovarian cancer patients with poor clinical outcome
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Katia Rea1, Patrizia Pinciroli2, Marialuisa Sensi2, Federica Alciato3, Brigitte Bisaro4, Ludmila Lozneanu5, Francesco Raspagliesi6, Floriana Centritto2, Sara Cabodi4, Paola Defilippi4, Gian Carlo Avanzi3, Silvana Canevari2, Antonella Tomassetti1
1Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2Functional Genomics and Bioinformatics Core Facility, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3Department of Traslational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy
4Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
5Department of Morphofunctional Sciences, Histology, Morphopatology, “Grigore T. Popa” University of Medicine and Pharmacy, Iassy, Romania
6Gynecology Oncology Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Antonella Tomassetti, e-mail: firstname.lastname@example.org
Keywords: Axl, Gas6, ovarian cancer, p130Cas, extracellular matrix
Received: June 12, 2015 Accepted: August 22, 2015 Published: September 04, 2015
High-grade epithelial ovarian cancer (HGEOC) is a clinically diverse and molecularly heterogeneous disease comprising subtypes with distinct biological features and outcomes. The receptor tyrosine kinases, expressed by EOC cells, and their ligands, present in the microenvironment, activate signaling pathways, which promote EOC cells dissemination. Herein, we established a molecular link between the presence of Gas6 ligand in the ascites of HGEOCs, the expression and activation of its receptor Axl in ovarian cancer cell lines and biopsies, and the progression of these tumors. We demonstrated that Gas6/Axl signalling converges on the integrin β3 pathway in the presence of the adaptor protein p130Cas, thus inducing tumor cell adhesion to the extracellular matrix and invasion. Accordingly, Axl and p130Cas were significantly co-expressed in HGEOC samples. Clinically, we identified an Axl-associated signature of 62 genes able to portray the HGEOCs with the shortest overall survival. These data biologically characterize a group of HGEOCs and could help guide a more effective therapeutic approach to be taken for these patients.
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