Abstract 49: ET-1 receptor blockade in engineered 3D high-grade serous ovarian cancer tumoroids

Abstract

Abstract High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by widespred and rapid metastatic nature, suggesting that unraveling determinants of metastasis may implement new therapeutic strategies on clinical care. In this tumor, autocrine or paracrine activation of the endothelin-1 receptors (ET-1R) are recognized drivers of tumor progression, promoting epithelial-mesenchymal transition (EMT), invasion, and metastasis, as well as tumor angiogenesis and lymphangiogenesis. However, since the metastatic spread and response to therapy are influenced by the extracellular matrix (ECM) density and composition of the surrounding tumour microenvironment (TME), the development of a three-dimensional in vitro model mimicking the in vivo tumors is necessary to better understand the dynamic interactions between tumor cells and TME elements, including fibroblasts, endothelial cells and the ECM, regulated by ET-1R. With this in mind, we have developed HG-SOC tumoroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel representing the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). After 21 days, ET-1-stimulated HG-SOC cells showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. As compared to control cells, ET-1 treated cells showed a higher number of cellular aggregates, which were reduced by treatment with the dual receptor antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared to control cells. These findings suggest that HG-SOC tumoroids might be useful to investigate the cross-talk between HG-SOC cells and TME in cancer progression and the response to combinatorial treatment, including ET-1R antagonist. Note: This abstract was not presented at the meeting. Citation Format: Laura Rosanò, Judith Pape, Umber Cheema, Marilena Loizidou, Anna Bagnato. ET-1 receptor blockade in engineered 3D high-grade serous ovarian cancer tumoroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 49.