(772b) Mechanical Tropism in Metastatic Ovarian Cancer Cells

Ovarian cancer is the fifth leading cause of cancer deaths among women, possibly because it is often diagnosed at late stages after metastasis (1). In contrast to following the normal metastatic process of intravasation to the vascular system and extravasation at a distal site, ovarian cancer is more likely to disseminate through the intraperitoneal fluids. From there, it preferentially accumulates in soft tissues such as the adipocyte-rich omentum (2). Previous work suggests this is because adipocytes act as a rich energy source and actively promote ovarian cancer cell homing via cytokines such as interleukin-8 (2). However, these studies were based solely on chemical factors, whereas the burgeoning field of physical oncology has recently shown the mechanical environment a cell experiences can be of equal importance. Based on these results, we hypothesized that the preferential accumulation of ovarian cancer cells in soft tissues may be due to intrinsic mechanical properties of the environment as opposed to the presence of soluble signaling molecules.

To test this hypothesis, we utilized a series of biophysical and biochemical techniques to understand the response of ovarian cancer cells to extracellular matrices of varying rigidities.  We found that ovarian cancer cells (OCCs) show increased adhesion to compliant matrices at short time scales coupled with increased spreading. After engraftment, OCCs on soft matrices are more proliferative and resistant to standard chemotherapeutic drugs. In addition to these increases in growth, cells also displayed increased migratory capacity. Further immunocytochemistry and gene expression analysis revealed a shift from a more epithelial phenotype on stiff substrates to a more mesenchymal phenotype on soft matrices.  Finally, biophysical characterization with small molecule inhibitors suggests the role of a Rho/ROCK mechanosensitive pathway in determining this tissue tropism.

1.   Landen, C.N., M.J. Birrer, and A.K. Sood. 2008. Early events in the pathogenesis of epithelial ovarian cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 26: 995–1005.

2.   Nieman, K.M., H. a Kenny, C. V Penicka, A. Ladanyi, R. Buell-Gutbrod, et al. 2011. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature medicine. 17: 1498–503.