Abstract B60: Identification of an ovarian tumor:stromal HH:BMP4 signaling loop critical to ovarian cancer growth and chemotherapy resistance.

Abstract

Abstract The ovarian tumor microenvironment is critical to ovarian cancer growth, spread, and survival. We recently identified a novel host cell component of the tumor microenvironment, human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are of particular interest as they are multi-potent and can differentiate to create many components of the tumor microenvironment including fibroblasts, myofibroblasts and adipocytes. CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We now define a CA-MSC BMP4: ovarian tumor cell Hedgehog (HH) positive feedback loop critical to the cancer promoting functions of CA-MSCs. We demonstrate that CA-MSC expression of BMP4 is induced by ovarian tumor cell-secreted Hedgehog (HH). Reciprocally, CA-MSC-derived BMP4 increases ovarian tumor cell HH expression creating a positive feedback loop. Interruption of this loop with either a HH pathway inhibitor (IPI-926 or LDE-225) or BMP4 blocking antibody decreases the induction of CA-MSC-derived BMP4 and tumor-derived HH. This signaling loop is critical to the pro-tumorigenic effects of CA-MSCs as HH inhibition blocked CA-MSC-mediated tumorigenesis and reduced the number of CSCs. Additionally, HH inhibition reversed CA-MSC -induced chemotherapy resistance leading to significant cisplatin response in established platinum-resistant tumors. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH providing further support for clinical targeting of the HH pathway, particularly in combination with platinum-based chemotherapy, in ovarian cancer. Citation Format: Lan G. Coffman, Yunjung Choi, Karen Mclean, Marina Pasca di Magliano, Benjamin Allen, Ronald J. Buckanovich. Identification of an ovarian tumor:stromal HH:BMP4 signaling loop critical to ovarian cancer growth and chemotherapy resistance. [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 B60.