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The multicellular signalling network of ovarian cancer metastases.
Sommerfeld, Leah; Finkernagel, Florian; Jansen, Julia M; Wagner, Uwe; Nist, Andrea; Stiewe, Thorsten; Müller-Brüsselbach, Sabine; Sokol, Anna M; Graumann, Johannes; Reinartz, Silke; Müller, Rolf.
Affiliation
  • Sommerfeld L; Department of Translational Oncology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
  • Finkernagel F; Department of Translational Oncology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
  • Jansen JM; Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, University Hospital (UKGM), Marburg, Germany.
  • Wagner U; Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, University Hospital (UKGM), Marburg, Germany.
  • Nist A; Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
  • Stiewe T; Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
  • Müller-Brüsselbach S; Institute of Molecular Oncology, Philipps University, Marburg, Germany.
  • Sokol AM; Department of Translational Oncology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
  • Graumann J; The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • Reinartz S; The German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • Müller R; Institute for Translational Proteomics, Philipps University, Marburg, Germany.
Clin Transl Med ; 11(11): e633, 2021 11.
Article in En | MEDLINE | ID: mdl-34841720
BACKGROUND: Transcoelomic spread is the major route of metastasis of ovarian high-grade serous carcinoma (HGSC) with the omentum as the major metastatic site. 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. METHODS: Based on transcriptomic analysis of tumour cells, tumour-associated 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-metastatic functions, including tumour cell migration, pro-inflammatory signal transduction and TAM expansion. RESULTS: 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 (n = 176 vs. n = 13). 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-matrix-triggered 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-tumourigenic TAM proliferation in conjunction with high CSF1 expression by omental stroma cells and (iii) triggers pro-inflammatory signaling, at least in part via a HSP70-NF-κB pathway. CONCLUSIONS: 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Gene Regulatory Networks / Neoplasm Metastasis Limits: Female / Humans Language: En Journal: Clin Transl Med Year: 2021 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Gene Regulatory Networks / Neoplasm Metastasis Limits: Female / Humans Language: En Journal: Clin Transl Med Year: 2021 Document type: Article Affiliation country: Country of publication: