Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer

Abstract Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins a...

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Autores principales:	Virginie Mieulet, Camille Garnier, Yann Kieffer, Thomas Guilbert, Fariba Nemati, Elisabetta Marangoni, Gilles Renault, Foucauld Chamming’s, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/de9d7830ae0941bbbd8cf54c4242beb8
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spelling	oai:doaj.org-article:de9d7830ae0941bbbd8cf54c4242beb82021-12-02T12:11:50ZStiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer10.1038/s41598-021-83685-02045-2322https://doaj.org/article/de9d7830ae0941bbbd8cf54c4242beb82021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83685-0https://doaj.org/toc/2045-2322Abstract Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins and high content of cancer-associated fibroblasts. Using patient-derived xenograft mouse models of Mesenchymal and Non-Mesenchymal HGSOC, we show here that HGSOC exhibit distinct stiffness depending on their molecular subtype. Indeed, tumor stiffness strongly correlates with tumor growth in Mesenchymal HGSOC, while Non-Mesenchymal tumors remain soft. Moreover, we observe that tumor stiffening is associated with high stromal content, collagen network remodeling, and MAPK/MEK pathway activation. Furthermore, tumor stiffness accompanies a glycolytic metabolic switch in the epithelial compartment, as expected based on Warburg’s effect, but also in stromal cells. This effect is restricted to the central part of stiff Mesenchymal tumors. Indeed, stiff Mesenchymal tumors remain softer at the periphery than at the core, with stromal cells secreting high levels of collagens and showing an OXPHOS metabolism. Thus, our study suggests that tumor stiffness could be at the crossroad of three major processes, i.e. matrix remodeling, MEK activation and stromal metabolic switch that might explain at least in part Mesenchymal HGSOC aggressiveness.Virginie MieuletCamille GarnierYann KiefferThomas GuilbertFariba NematiElisabetta MarangoniGilles RenaultFoucauld Chamming’sAnne Vincent-SalomonFatima Mechta-GrigoriouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Virginie Mieulet Camille Garnier Yann Kieffer Thomas Guilbert Fariba Nemati Elisabetta Marangoni Gilles Renault Foucauld Chamming’s Anne Vincent-Salomon Fatima Mechta-Grigoriou Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer
description	Abstract Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins and high content of cancer-associated fibroblasts. Using patient-derived xenograft mouse models of Mesenchymal and Non-Mesenchymal HGSOC, we show here that HGSOC exhibit distinct stiffness depending on their molecular subtype. Indeed, tumor stiffness strongly correlates with tumor growth in Mesenchymal HGSOC, while Non-Mesenchymal tumors remain soft. Moreover, we observe that tumor stiffening is associated with high stromal content, collagen network remodeling, and MAPK/MEK pathway activation. Furthermore, tumor stiffness accompanies a glycolytic metabolic switch in the epithelial compartment, as expected based on Warburg’s effect, but also in stromal cells. This effect is restricted to the central part of stiff Mesenchymal tumors. Indeed, stiff Mesenchymal tumors remain softer at the periphery than at the core, with stromal cells secreting high levels of collagens and showing an OXPHOS metabolism. Thus, our study suggests that tumor stiffness could be at the crossroad of three major processes, i.e. matrix remodeling, MEK activation and stromal metabolic switch that might explain at least in part Mesenchymal HGSOC aggressiveness.
format	article
author	Virginie Mieulet Camille Garnier Yann Kieffer Thomas Guilbert Fariba Nemati Elisabetta Marangoni Gilles Renault Foucauld Chamming’s Anne Vincent-Salomon Fatima Mechta-Grigoriou
author_facet	Virginie Mieulet Camille Garnier Yann Kieffer Thomas Guilbert Fariba Nemati Elisabetta Marangoni Gilles Renault Foucauld Chamming’s Anne Vincent-Salomon Fatima Mechta-Grigoriou
author_sort	Virginie Mieulet
title	Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer
title_short	Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer
title_full	Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer
title_fullStr	Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer
title_full_unstemmed	Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer
title_sort	stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/de9d7830ae0941bbbd8cf54c4242beb8
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Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer

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