The multicellular signalling network of ovarian cancer metastases

Abstract 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 interc...

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Autores principales:	Leah Sommerfeld, Florian Finkernagel, Julia M. Jansen, Uwe Wagner, Andrea Nist, Thorsten Stiewe, Sabine Müller‐Brüsselbach, Anna M. Sokol, Johannes Graumann, Silke Reinartz, Rolf Müller
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	adipocyte carcinoma‐associated fibroblast HSP70 mesothelial cell metastasis omentum Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/5a67251726af44cc8db5008727a41277
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spelling	oai:doaj.org-article:5a67251726af44cc8db5008727a412772021-11-30T07:25:38ZThe multicellular signalling network of ovarian cancer metastases2001-132610.1002/ctm2.633https://doaj.org/article/5a67251726af44cc8db5008727a412772021-11-01T00:00:00Zhttps://doi.org/10.1002/ctm2.633https://doaj.org/toc/2001-1326Abstract 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.Leah SommerfeldFlorian FinkernagelJulia M. JansenUwe WagnerAndrea NistThorsten StieweSabine Müller‐BrüsselbachAnna M. SokolJohannes GraumannSilke ReinartzRolf MüllerWileyarticleadipocytecarcinoma‐associated fibroblastHSP70mesothelial cellmetastasisomentumMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	adipocyte carcinoma‐associated fibroblast HSP70 mesothelial cell metastasis omentum Medicine (General) R5-920
spellingShingle	adipocyte carcinoma‐associated fibroblast HSP70 mesothelial cell metastasis omentum Medicine (General) R5-920 Leah Sommerfeld Florian Finkernagel Julia M. Jansen Uwe Wagner Andrea Nist Thorsten Stiewe Sabine Müller‐Brüsselbach Anna M. Sokol Johannes Graumann Silke Reinartz Rolf Müller The multicellular signalling network of ovarian cancer metastases
description	Abstract 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.
format	article
author	Leah Sommerfeld Florian Finkernagel Julia M. Jansen Uwe Wagner Andrea Nist Thorsten Stiewe Sabine Müller‐Brüsselbach Anna M. Sokol Johannes Graumann Silke Reinartz Rolf Müller
author_facet	Leah Sommerfeld Florian Finkernagel Julia M. Jansen Uwe Wagner Andrea Nist Thorsten Stiewe Sabine Müller‐Brüsselbach Anna M. Sokol Johannes Graumann Silke Reinartz Rolf Müller
author_sort	Leah Sommerfeld
title	The multicellular signalling network of ovarian cancer metastases
title_short	The multicellular signalling network of ovarian cancer metastases
title_full	The multicellular signalling network of ovarian cancer metastases
title_fullStr	The multicellular signalling network of ovarian cancer metastases
title_full_unstemmed	The multicellular signalling network of ovarian cancer metastases
title_sort	multicellular signalling network of ovarian cancer metastases
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/5a67251726af44cc8db5008727a41277
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The multicellular signalling network of ovarian cancer metastases

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