The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
| Autor: | Zöe L. Edmunds, Kathryn V Svec, Stephanie R. Hicks, Alan K. Howe, Andrew J. McKenzie, Hannah Naughton |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cellular pathology endocrine system diseases Cell Cycle Proteins Carcinoma Ovarian Epithelial Cell morphology Mechanotransduction Cellular Metastasis Extracellular matrix Mice 0302 clinical medicine Cell Movement Tumor Microenvironment Phosphorylation Mechanotransduction Ovarian Neoplasms rho-Associated Kinases 0303 health sciences Multidisciplinary Durotaxis Chemistry Nuclear Proteins Cell migration Actomyosin female genital diseases and pregnancy complications Biomechanical Phenomena Extracellular Matrix Cell biology Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Medicine Female Peritoneum Myosin Light Chains Science Article 03 medical and health sciences Cell Line Tumor Elastic Modulus Spheroids Cellular medicine Animals Humans 030304 developmental biology Focal Adhesions Tumor microenvironment Spheroid medicine.disease Mice Inbred C57BL 030104 developmental biology Focal Adhesion Kinase 1 Transcription Factors |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-20 (2018) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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