The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation

Abstract There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we inves...

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Autores principales:	Andrew J. McKenzie, Stephanie R. Hicks, Kathryn V. Svec, Hannah Naughton, Zöe L. Edmunds, Alan K. Howe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e188616ed8974641a305dd3aa2218f57
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spelling	oai:doaj.org-article:e188616ed8974641a305dd3aa2218f572021-12-02T12:32:48ZThe mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation10.1038/s41598-018-25589-02045-2322https://doaj.org/article/e188616ed8974641a305dd3aa2218f572018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25589-0https://doaj.org/toc/2045-2322Abstract There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we investigated the effect of substrate rigidity on various aspects of SKOV3 human EOC cell morphology and migration. Young’s modulus values of normal mouse peritoneum, a principal target tissue for EOC metastasis, were determined by atomic force microscopy (AFM) and hydrogels were fabricated to mimic these values. We find that cell spreading, focal adhesion formation, myosin light chain phosphorylation, and cellular traction forces all increase on stiffer matrices. Substrate rigidity also positively regulates random cell migration and, importantly, directional increases in matrix tension promote SKOV3 cell durotaxis. Matrix rigidity also promotes nuclear translocation of YAP1, an oncogenic transcription factor associated with aggressive metastatic EOC. Furthermore, disaggregation of multicellular EOC spheroids, a behavior associated with dissemination and metastasis, is enhanced by matrix stiffness through a mechanotransduction pathway involving ROCK, actomyosin contractility, and FAK. Finally, this pattern of mechanosensitivity is maintained in highly metastatic SKOV3ip.1 cells. These results establish that the mechanical properties of the tumor microenvironment may play a role in EOC metastasis.Andrew J. McKenzieStephanie R. HicksKathryn V. SvecHannah NaughtonZöe L. EdmundsAlan K. HoweNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-20 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrew J. McKenzie Stephanie R. Hicks Kathryn V. Svec Hannah Naughton Zöe L. Edmunds Alan K. Howe The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
description	Abstract There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we investigated the effect of substrate rigidity on various aspects of SKOV3 human EOC cell morphology and migration. Young’s modulus values of normal mouse peritoneum, a principal target tissue for EOC metastasis, were determined by atomic force microscopy (AFM) and hydrogels were fabricated to mimic these values. We find that cell spreading, focal adhesion formation, myosin light chain phosphorylation, and cellular traction forces all increase on stiffer matrices. Substrate rigidity also positively regulates random cell migration and, importantly, directional increases in matrix tension promote SKOV3 cell durotaxis. Matrix rigidity also promotes nuclear translocation of YAP1, an oncogenic transcription factor associated with aggressive metastatic EOC. Furthermore, disaggregation of multicellular EOC spheroids, a behavior associated with dissemination and metastasis, is enhanced by matrix stiffness through a mechanotransduction pathway involving ROCK, actomyosin contractility, and FAK. Finally, this pattern of mechanosensitivity is maintained in highly metastatic SKOV3ip.1 cells. These results establish that the mechanical properties of the tumor microenvironment may play a role in EOC metastasis.
format	article
author	Andrew J. McKenzie Stephanie R. Hicks Kathryn V. Svec Hannah Naughton Zöe L. Edmunds Alan K. Howe
author_facet	Andrew J. McKenzie Stephanie R. Hicks Kathryn V. Svec Hannah Naughton Zöe L. Edmunds Alan K. Howe
author_sort	Andrew J. McKenzie
title	The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
title_short	The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
title_full	The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
title_fullStr	The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
title_full_unstemmed	The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
title_sort	mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/e188616ed8974641a305dd3aa2218f57
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The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation

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