Ovarian Cancer Spheroids Use Myosin-Generated Force to Clear the Mesothelium

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Abstract
Dissemination of ovarian tumors involves the implantation of cancer spheroids into the mesothelial monolayer on the walls of peritoneal and pleural cavity organs. Biopsies of tumors attached to peritoneal organs show that mesothelial cells are not present under tumor masses. We have developed a live, image-based in vitro model in which interactions between tumor spheroids and mesothelial cells can be monitored in real time to provide spatial and temporal understanding of mesothelial clearance. In this article, we provide evidence that ovarian cancer spheroids use integrin- and talin-dependent activation of myosin and traction force to promote displacement of mesothelial cells from underneath a tumor cell spheroid. These results suggest that ovarian tumor cell clusters gain access to the submesothelial environment by exerting force on the mesothelial cells lining target organs, driving migration and clearance of the mesothelial cells. Significance: This study uses time-lapse video microscopy to decipher cellular events associated with ovarian tumor cell intercalation of mesothelial cell layers. Ovarian cancer clusters were found to use actomyosin-generated force to physically displace mesothelial cells and gain access to the submesothelial environment. Blockade of force-conducting molecules, including α5 integrin, talin I, and nonmuscle myosin II, in cancer cells abrogated mesothelial displacement from underneath attached cancer spheroids. Cancer Discovery; 1(2); 144–57. ©2011 AACR. Read the Commentary on this article by Kenny et al., p. 100 This article is highlighted in the In This Issue feature, p. 91