Role of ANGPTL4 in ovarian carcinoma

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Ovarian carcinoma (OC) is the most frequent cause of death from a gynecological malignancy. Among the unique features of this disease is its tumor microenvironment, which is comprised by the tumor stroma and the peritoneal fluid (occurring as ascites at advanced stages). The peritoneal fluid is rich in soluble factors, cancer cell spheroids and different types of reeducated host cells that cooperate to establish an environment promoting peritoneal dissemination and immune suppression. Our previous work has established a comprehensive signaling network operating between tumor and host cells in OC ascites and has identified ANGPTL4 as a component within this network. ANGPTL4 is strongly induced by ascites, promotes OC cell invasion and is associated with a poor survival. Nevertheless, the precise role of ANGPTL4 in the metastatic spread of OC cells to peritoneal organs remains unclear. Thus, the potential function of ANGPTL4 in the attachment of OC cancer cells to the mesothelial lining of these organs, in their invasion of the mesothelium and submesothelial layers, in the induction of epithelial-to-mesenchymal transition (EMT) and in the secretion of metastasis-relevant cytokines remain obscure. In the proposed project we intend to shed light on these open questions.ANGPTL4 exerts its pro-invasive properties through binding to membrane receptors (integrins). However, the molecular signaling mechanisms utilized by ANGPTL4 to promote the pro-metastatic properties of OC cells are largely unknown. We therefore intend to link the pro-metastatic functions of ANGPTL4 alluded to above with specific signal transduction pathways. Towards this goal, we will apply (i) a hypothesis-driven approach to analyze the activation state of proteins previously proposed as ANGPTL4-triggered signal transducers, and (ii) an unbiased strategy based on transcriptomics and phosphoproteomics. The central goal of this project is to test the hypothesis that ANGPTL4-induced signaling plays an essential role in OC invasion and metastasis and therefore represents a potential pharmacological target for therapeutic intervention. We will address this question by interfering with its expression or function and determining the impact of this blockade on the ascites-induced pro-metastatic biological functions of OC cells. All studies for this project will be carried out with patient-derived tumor cells and will be complemented by studies in mouse models of peritoneal dissemination.