Abstract A31: Mutant p53 increases integrin-ECM interactions in early HGSOC

Abstract

Abstract Until recently, it was thought that high-grade serous ovarian cancer (HGSOC) arises from the ovarian surface epithelium (OSE). Now, it has become clear that the epithelium of the fallopian tube fimbriae is the starting point of many HGSOCs. Serous tubal intraepithelial carcinomas (STICs) are suggested to be the earliest form of HGSOC and show mutations in the p53 gene. Part of the neoplastic transformation into invasive HGSOC may be the initial adhesion of STIC cells to the surface of the ovary as a first site of metastasis. To examine the role of mutant p53 immortalized fallopian tube secretory epithelial (FTSE) cells in the early onset of HGSOC, we used mechanically tunable hydrogels and developed a protocol to obtain decellularized human ovary scaffolds for 3D cell cultures. Stable expression of mutant p53 in FTSE cells promoted adhesion to hydrogel matrices and invasion into decellularized ovary scaffolds. Next, we sought to analyze the extracellular matrix (ECM) landscape of human fallopian tube and ovary tissues and identified proteins with a high affinity to integrin αvβ3. Mutant p53 FTSE cells had increased levels of integrin αvβ3 and decreased adhesive potential upon integrin αvβ3 blockage compared to wild-type FTSE cells. The results indicate that FTSE cells expressing mutant p53 upregulate integrin expression, which in turn alters their tissue-specific ECM interactions. Our findings give new insights in the early onset of HGSOC and may help to understand the role of p53 in the cells of origin of HGSOC. Citation Format: Laura SM Lecker, Caterina Trevisan, Robin Delaine-Smith, Eleni Maniati, Oliver Pearce, Christoph Meinert, Marcin Iwanicki, Ronny Drapkin, Daniela Loessner, Frances Balkwill. Mutant p53 increases integrin-ECM interactions in early HGSOC. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A31.