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Magdalena Huber / Rolf Müller: Intercellular signaling mediated by pro-inflammatory IL17A/F in ovarian cancer

Magdalena Huber/Rolf Müller will dissect IL-17A/F-driven signaling in ovarian carcinoma including the identification of the cellular source and its impact on NF-κB signaling in tumor and tumor-associated host cells. This project is based on previous work demonstrating that high expression of the IL-17 receptor subunit C (IL-17RC) is strongly associated with poor relapse-free survival in ovarian carcinoma (not published). IL-17A and IL-17F are cytokines binding to the IL-17R receptor, which specific IL-17RC subunit is probably upregulated on tumor as well as tumor-associated cells in the ovarian cancer microenvironment by FSTL1. IL-17R triggers multiple pro-inflammatory signal transduction pathways, in particular NF-κB. This project aims to (i) identify the immune cells producing IL-17A/F in ovarian cancer, (ii) study IL-17RC regulation in tumor and tumor-associated host cells, and (iii) study effects of IL-17A/F directly on tumor cells or indirectly via mediators secreted by tumor-associated cells and their association with RFS. It is anticipated that this work will lead to the identification of potential therapeutic targets and inhibitors able to interfere with IL-17RC-induced signaling.

Model of the FSTL1 – IL17RC – IL17A/F regulatory circuit in the OC microenvironment.
FSTL-1 induces expression of the IL-17 receptor (IL17RC) in tumor, mesothelial cells, adipocytes, and macrophages. Binding of IL17A/F to IL-17RC activates pro-inflammatory signaling cascades including NF-κB to directly or indirectly enhance tumorigenicity of cancer cells leading to shortened RFS. The source of IL-17A/F has to be defined.