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

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 t...

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Autores principales: McKenzie, Andrew J., Hicks, Stephanie R., Svec, Kathryn V., Naughton, Hannah, Edmunds, Zöe L., Howe, Alan K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940803/
https://www.ncbi.nlm.nih.gov/pubmed/29740072
http://dx.doi.org/10.1038/s41598-018-25589-0
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author McKenzie, Andrew J.
Hicks, Stephanie R.
Svec, Kathryn V.
Naughton, Hannah
Edmunds, Zöe L.
Howe, Alan K.
author_facet McKenzie, Andrew J.
Hicks, Stephanie R.
Svec, Kathryn V.
Naughton, Hannah
Edmunds, Zöe L.
Howe, Alan K.
author_sort McKenzie, Andrew J.
collection PubMed
description 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.
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spelling pubmed-59408032018-05-11 The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation McKenzie, Andrew J. Hicks, Stephanie R. Svec, Kathryn V. Naughton, Hannah Edmunds, Zöe L. Howe, Alan K. Sci Rep Article 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. Nature Publishing Group UK 2018-05-08 /pmc/articles/PMC5940803/ /pubmed/29740072 http://dx.doi.org/10.1038/s41598-018-25589-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
McKenzie, Andrew J.
Hicks, Stephanie R.
Svec, Kathryn V.
Naughton, Hannah
Edmunds, Zöe L.
Howe, Alan K.
The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940803/
https://www.ncbi.nlm.nih.gov/pubmed/29740072
http://dx.doi.org/10.1038/s41598-018-25589-0
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