title: Novel Axl-driven signaling pathway and molecular signature characterize high-grade ovarian cancer patients with poor clinical outcome.
abstract: 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.
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Rea
authors.affiliation: Functional Genomics and Bioinformatics Core Facility, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pinciroli
authors.affiliation: Functional Genomics and Bioinformatics Core Facility, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sensi
authors.affiliation: Department of Traslational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Alciato
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bisaro
authors.affiliation: Department of Morphofunctional Sciences, Histology, Morphopatology, "Grigore T. Popa" University of Medicine and Pharmacy, Iassy, Romania.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Lozneanu
authors.affiliation: Gynecology Oncology Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Raspagliesi
authors.affiliation: Functional Genomics and Bioinformatics Core Facility, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Centritto
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Defilippi
authors.affiliation: Department of Traslational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy.
authors.forename: Gian Carlo
authors.initials: GC
authors.lastname: Avanzi
authors.affiliation: Functional Genomics and Bioinformatics Core Facility, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tomassetti
mesh_terms: D001201:Ascites / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D000077216:Carcinoma, Ovarian Epithelial; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011237:Predictive Value of Tests; D060066:Protein Interaction Maps; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D014408:Biomarkers, Tumor; D050719:Crk-Associated Substrate Protein; D039661:Integrin beta3; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C493841:BCAR1 protein, human; C061248:ITGB3 protein, human; C000722289:AXL protein, human
keywords: Axl; Gas6; extracellular matrix; ovarian cancer; p130Cas