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Its unique tumour microenvironment with its large populations of adipocytes, mesothelial cells and immune cells establishes an intercellular signaling network that is instrumental for metastatic growth yet poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Based on transcriptomic analysis of tumour cells, tumour\u2010associated immune and stroma cells we defined intercellular signaling pathways for 284 cytokines and growth factors and their cognate receptors after bioinformatic adjustment for contaminating cell types. The significance of individual components of this network was validated by analysing clinical correlations and potentially pro\u2010metastatic functions, including tumour cell migration, pro\u2010inflammatory signal transduction and TAM expansion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The data show an unexpected prominent role of host cells, and in particular of omental adipocytes, mesothelial cells and fibroblasts (CAF), in sustaining this signaling network. These cells, rather than tumour cells, are the major source of most cytokines and growth factors in the omental microenvironment (<jats:italic>n<\/jats:italic>\u00a0=\u00a0176 vs. <jats:italic>n<\/jats:italic>\u00a0=\u00a013). Many of these factors target tumour cells, are linked to metastasis and are associated with a short survival. Likewise, tumour stroma cells play a major role in extracellular\u2010matrix\u2010triggered signaling. We have verified the functional significance of our observations for three exemplary instances. We show that the omental microenvironment (i) stimulates tumour cell migration and adhesion via WNT4 which is highly expressed by CAF; (ii) induces pro\u2010tumourigenic TAM proliferation in conjunction with high CSF1 expression by omental stroma cells and (iii) triggers pro\u2010inflammatory signaling, at least in part via a HSP70\u2013NF\u2010\u03baB pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The intercellular signaling network of omental metastases is majorly dependent on factors secreted by immune and stroma cells to provide an environment that supports ovarian HGSC progression. Clinically relevant pathways within this network represent novel options for therapeutic intervention.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.633","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T15:37:42Z","timestamp":1636385862000},"source":"Crossref","is-referenced-by-count":26,"title":["The multicellular signalling network of ovarian cancer metastases"],"prefix":"10.1002","volume":"11","author":[{"given":"Leah","family":"Sommerfeld","sequence":"first","affiliation":[{"name":"Department of Translational Oncology, Center for Tumor Biology and Immunology (ZTI) Philipps University  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Finkernagel","sequence":"additional","affiliation":[{"name":"Department of Translational Oncology, Center for Tumor Biology and Immunology (ZTI) Philipps University  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia 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