The intercellular signaling network in the tumor microenvironment of ovarian high-grade serous carcinoma
Ovarian high-gradeserous carcinoma (HGSC) is one of the most fatal malignancies in women. For this reason,it is of great importance to discover new potential targets for therapeutic intervention.Transcoelomic spread of tumor cells via malignant ascites,particularly to the omentum,is the major route...
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|Ovarian high-gradeserous carcinoma (HGSC) is one of the most fatal malignancies in women. For this reason,it is of great importance to discover new potential targets for therapeutic intervention.Transcoelomic spread of tumor cells via malignant ascites,particularly to the omentum,is the major route of HGSC metastasis. HGSC is characterized by its unique tumor microenvironment, consisting of two different anatomic compartments,i.e., ascites and solid tumor lesions, which are both composed of tumor and host cells. Although there are several published studies on signaling networks between ascites cells, the pathways of host-tumor interactions in omental metastases, as well as across different tumor microenvironment compartments, are largely unexplored. Therfore, the primary aim of this work was to establish a comprehensive network of cytokines, growth factors, lipid-mediators and extracellular matrix components, secreted by tumor and host cells, and their corresponding receptors in the HGSC tumor microenvironment. A transcriptomic analysis within this study uncovered an unexpected major function of tumor-associated stroma and immune cells within this network, being the predicted key source of most cytokines, growth factors and extracellular matrix proteins. While 176 cytokines and growth factors were selectively expressed by stroma and tumor-associated immune cells, only 13 were tumor-cell-selective. Many of these mediators are significantly associated with a poor clinical outcome and are linked to metastasis. We also found cell-type-selective pathways within the HGSC tumor microenvironment, some of which were further analyzed in functional studies.
Functional studies demonstrated that CAF stimulate tumor cell migration and adhesion to a mesothelial monolayer via the highly cell-type-selective secretion of the ligand WNT4. Additionally, both TNC and TGFBI secreted by ascites-derived TAM (ascTAM) were found to play a potentially pivotal role in HGSC progression by enhancing tumor cell migration. Apart from cytokines and growth factors, we also investigated the role for tumor-associated host cells in lipid-mediated signaling. We detected a cell-type-selective production of prostacyclin (PGI2) by omental CAF and mesothelial cells. Due to high expression and ligand-induced activation of the corresponding PGI2 receptor, TAM were identified as a potential target cell population. Using a PGI2 analog, we observed a shift of the differentiation state and transcriptional profile of ascTAM towards a mixed-polarization phenotype with immunosuppressive characteristics. Furthermore, PGI2 analoga reduced the phagocytic capability of TAM-like macrophages that were derived from monocytes differentiated in the presence of ascites. Moreover, a potential role for the PGI2-regulated secretome in metastatic growth was revealed by experiments showing an increase in tumor cell migration and adhesion to mesothelial cells by conditioned medium from PGI2-treated TAM. Taken together, these findings indicate that omental immune and stromal cells play an essential role in biological process linked to HGSC progression.