Abstract 923: Exploring the role of the ovarian stromal extracellular matrix in early tumor development

Background: Advancements in ovarian cancer research have shown evidence for extra-ovarian origins of malignant cells. The fallopian tubes (FT) are thought to be a source of the most common and aggressive type of ovarian tumor, high grade serous which are more common in women with increased ovulation. We have previously demonstrated that the ovulation wound site provides an ideal environment for malignant FT cells to implant into the ovary (1). However, while malignant cells implant during the reproductive stage, the highest instance of ovarian cancer occurs in peri- and postmenopausal women. We hypothesize that the ovarian environment provides the necessary factors to keep implanted malignant cells quiescent until peri- and post-menopause when the changes in the ovarian environment trigger proliferation and growth. The extracellular matrix (ECM), secreted by the ovarian stroma, is a major part of this environment which regulates cell-to-cell communication and maintains structural integrity. The intent of this study is to determine the critical role of the pre- and postmenopausal ECM and elucidate the effects of matrix remodelling on malignant cells. Methods: We generated malignant cells by introducing p53 mutations to healthy FT and ovarian surface epithelial (OSE) cell lines. In vitro, we isolated ECM from pre-menopausal ovarian stroma. Additionally, we overexpressed matrix metalloproteinase 2/9 (MMP2/9) in stromal cells to induce matrix remodelling, resulting in an ECM resembling postmenopause. These matrices were used to develop a new 3D culture method which allowed us to evaluate the effect menopausal ECM remodelling has on malignant cell pathways. Results: The 3D ovarian stromal ECM maintained and delayed growth of the co-cultured malignant cells compared to their monolayer counterparts. Postmenopausal remodelling of the ECM, via upregulation of MMPs, triggered proliferation and expansion of malignant cells. We discovered, through pathway screening, that AKT, ERK 1/2, PTEN, WNT and PYK2 were associated with these ECM-related changes in the malignant cells. Conclusion: These results support the use of a 3D model in culturing pre-tumor cells to create an in vitro model that closely resembles an ovarian environment. We have also shown that the ECM plays a role in maintaining malignant cells by supressing proliferation and growth. Additionally, we have demonstrated that the remodelling of the ECM that occurs with menopause-associated increase in MMP2/9 expression triggers expansion of malignant cells. It is clear that the ECM plays an important role in the early development of ovarian cancer and that MMP could be a contributing factor to the postmenopausal presentation of these malignancies. Going forward, we plan to further elucidate the specific molecular mechanisms involved in postmenopausal tumor development. Citation Format: Jamie T. Goodner-Bingham, Yang Yang-Hartwich. Exploring the role of the ovarian stromal extracellular matrix in early tumor development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 923.