Abstract B57: Continuous exposure to epidermal growth factor in ovarian cancer cells causes a persistent increase in N-cadherin expression which then results in multicellular aggregate compaction

Ovarian cancer is the leading cause of death arising from gynecological malignancies. Overexpression of the epidermal growth factor receptor (EGFR) or its ligands is associated with poor prognosis. The presence of EGFR activators in patient ascites fluid may lead to constitutive activation of the EGFR and thereby contribute to metastasis and/or resistance to therapy. Acquired chemoresistance following initial chemotherapeutic treatment prevents clinical effectiveness and occurs in a large majority of patients. Thus, our studies evaluated the cellular consequences to prolonged EGF exposure/EGFR activation and how this could contribute to metastasis or chemoresistance. We found that extended exposure to EGF (10 nM, ~40 days) resulted in a change in cell phenotype that was retained even when the EGF ligand was removed for at least 7 days (removal). There was a persistent increase in N-cadherin and vimentin levels in EGF treated and removal cells. This increase in mesenchymal markers in EGF treated cells is associated with a significant increase in multicellular aggregate (MCA) compaction. Furthermore, EGF treated MCAs displayed a significant increase in cell spreading when allowed to adhere to collagen. MCA compaction and enhanced spreading were largely due to elevated N-cadherin levels as we found that knock down of N-cadherin resulted in less compact MCAs and reduced spreading on collagen. MCAs have been shown to be chemoresistant and the compact MCA structure due to prolonged EGF treatment conferred resistance to cisplatin treatment. Our results indicate that prolonged EGFR activation causes a persistent change in mesenchymal marker expression, which regulates MCA compaction and sensitivity to chemotherapeutics. This finding suggests that activators of the EGFR in the tumor environment may drive changes in ovarian cancer cells that contribute to the low patient survival rates. Citation Format: Sabrina L. Samudio-Ruiz, Laurie G. Hudson. Continuous exposure to epidermal growth factor in ovarian cancer cells causes a persistent increase in N-cadherin expression which then results in multicellular aggregate compaction. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B57.