Metastatic ovarian cancer cell malignancy 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 lessmetastatic OCCs. Finally, we demonstrate that this mechanical tropism is governed through a Rho-ROCK signaling pathway.

RhoGTPases – A novel link between cytoskeleton organization and cisplatin resistance

“…Following engraftment, metastatic ovarian cancer cells cultured on soft matrices were shown to have higher resistance to chemotherapeutic drugs, a mechanical tropism that was shown to be mediated by the Rho/ROCK signaling pathway (McGrail et al, 2014). These results reinforce the idea that mechanical signals are a key factor in cancer progression and chemoresistance.…”

“…Another recent study has shown that metastatic ovarian cancer cells undergo changes in cytoskeleton organization and exhibit increased adhesion on soft microenvironments (McGrail et al, 2014). Following engraftment, metastatic ovarian cancer cells cultured on soft matrices were shown to have higher resistance to chemotherapeutic drugs, a mechanical tropism that was shown to be mediated by the Rho/ROCK signaling pathway (McGrail et al, 2014).…”

The 2016 John J. Abel Award Lecture: Targeting the Mechanical Microenvironment in Cancer

“…Interestingly, ovarian cancer cells were shown to present opposite responses to matrix rigidities-these cancer cells preferentially adhere to softer ECM and present an enhanced invasive phenotype when cultured on softer substrates through RHO/ROCK signaling pathways (McGrail et al, 2014). This supports the notion that multiple mechanosensing mechanisms exist among different cell types possibly due to the different mechanical environments of their tissues of origin.…”

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

“…These findings demonstrated the importance of substrate stiffness on ovarian cancer cell phenotype, differing metastatic potentials between cell lines, and the incorporation of the Rho/ROCK pathway in ovarian cancer mechanotransduction. 92 To evaluate the importance of investigating cellular-ECM interactions in a 3D environment, varying stiffness 3D constructs were studied by Zhang et al, 93 Loessner et al, 94 and Guo et al 95 The work of Zhang and Loessner both utilized PEG constructs. Zhang et al investigated hydrogels with three stiffnesses and found that the epithelial ovarian papillary serous cystadenocarcinoma cell line, 96 HO8910, grew the fastest, formed multicellular spheroids, and adhered preferentially to the medium hydrogel stiffness, of 12 kPa.…”

“…101,102 As ovarian cancer experiences an environment with variable stiffness, the YAP/TAZ pathway is a point of interest for future mechanotransduction studies. The Rho/ Rock pathway has already been tied to stiffness effects on ovarian cancer cells 92 and it has been established as a well-known factor in both mechanotransduction and cancer progression for a variety of tumor types. [103][104][105][106][107] Caveolin-1 has been shown to be essential for stiffness sensing, and thus when silenced, tumor cells are able to proliferate and migrate independent of the rigidity of the surrounding ECM.…”