High-grade serous ovarian cancer (HGS-OvCa) harbor p53 mutations and predominantly originates from the secretory epithelial cell compartment of the fallopian tube fimbriae. From this site, tumor cells detach, survive in the peritoneal cavity, and form cellular clusters that clear the mesothelium and expand to form peritoneal masses. To examine the contribution of mutant p53 to any of these phenotypic alterations associated with HGS-OvCA tumor progression, we developed live-cell microscopy assays that recapitulate these phenotypes and examined dynamic processes regulated by depletion of p53 or gain-of-function (GOF) mutations in p53 in cultured secretory fallopian tube epithelial cells. Expression of GOF mutant variants of p53, but not depletion of endogenous wild-type p53, promoted survival and cell-cell aggregation under conditions of cell detachment, leading to the formation of spheroids with mesothelium-clearing capacity. These phenotypes were blocked by mutant p53 reactivation and depended on the expression of the mesenchyme transcription factor TWIST1, inhibition of p63 and de novo formation of a unique cell-matrix adhesion niche supported by autocrine fibronectin production and activation of integrins in detached cells. Inhibition of fibronectin or integrin α5 in suspension blocked cell-to-cell adhesion leading to HGS-OvCa spheroid disintegration and ultimately anoikis. These results indicate the detached FTE cells-expressing GOF mutants of p53 undergo a mesenchymal transition under conditions of matrix detachment leading to autocrine production of matrix and anchorage-independent survival and proliferation, as well as mesothelial clearance activity. These findings provide important new insights into activities of mutant p53 that may play a critical role in early events in tumorigenesis of high-grade ovarian serous tumors and provide a rationale for the development of therapeutics that target ovarian cancer cells transiting through the peritoneal cavity.
This abstract is also presented as Poster B03.
Citation Format: Marcin P. Iwanicki, Hsing-Yu Chen, Ioannis Zervantonakis, Marian Novak, Taru Muranen, Tan A. Ince, Ronny Drapkin, Joan S. Brugge. Mutant p53 drives early events in fallopian tube tumorigenesis through mesenchyme-associated autocrine production of matrix that supports survival and mesothelial intercalation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR12.