title: The malignancy of metastatic ovarian cancer cells is increased on soft matrices through a mechanosensitive Rho-ROCK pathway.
abstract: Although current treatments for localized ovarian cancer are highly effective, this cancer still remains the most lethal gynecological malignancy, largely owing to the fact that it is often detected only after tumor cells leave the primary tumor. Clinicians have long noted a clear predilection for ovarian cancer to metastasize to the soft omentum. Here, we show that this tropism is due not only to chemical signals but also mechanical cues. Metastatic ovarian cancer cells (OCCs) preferentially adhere to soft microenvironments and display an enhanced malignant phenotype, including increased migration, proliferation and chemoresistance. To understand the cell-matrix interactions that are used to sense the substrate rigidity, we utilized traction force microscopy (TFM) and found that, on soft substrates, human OCCs increased both the magnitude of traction forces as well as their degree of polarization. After culture on soft substrates, cells underwent morphological elongation characteristic of epithelial-to-mesenchymal transition (EMT), which was confirmed by molecular analysis. Consistent with the idea that mechanical cues are a key determinant in the spread of ovarian cancer, the observed mechanosensitivity was greatly decreased in less-metastatic OCCs. Finally, we demonstrate that this mechanical tropism is governed through a Rho-ROCK signaling pathway.
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McGrail
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Quang Minh N
authors.initials: QM
authors.lastname: Kieu
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA The Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA mdawson@gatech.edu.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Dawson
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D003470:Culture Media; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006244:Hardness; D006801:Humans; D040542:Mechanotransduction, Cellular; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000473:pathology*; D010641:Phenotype; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D003470:Culture Media; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins
keywords: Mechanotransduction; Ovarian cancer metastasis; Tissue tropism
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