Stromal cell DDR2 promotes ovarian cancer metastasis

Abstract Ovarian cancer is the leading cause of gynecological cancer-related deaths. The propensity for metastasis within the peritoneal cavity is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. In this study we investigate the contribution of stromal cells to ovarian cancer metastasis and identify normal stromal cell expression of the collagen receptor, Discoidin Domain Receptor 2 (DDR2), that acts to facilitate ovarian cancer metastasis. In vivo, global genetic inactivation of Ddr2 impairs the ability of Ddr2-expressing syngeneic ovarian cancer cells to spread throughout the peritoneal cavity. Therefore, we wanted to further investigate how various DDR2-expressing stromal cells may individually be contributing to ovarian cancer metastasis. First, we investigated mesothelial cells, as these are one of the first cell types that ovarian cancer cells interact with during metastasis. We find that DDR2 expression in mesothelial cells lining the peritoneal cavity facilitates tumor cell attachment and clearance. To examine the contribution of DDR2 expression in mesothelial cells in vivo, we have generated and validated a mouse model in which Ddr2 is specifically knocked out in mesothelial cells. We have ongoing experiments to determine whether inhibition of DDR2 in just mesothelial cells decreases ovarian tumor cell attachment and tumor burden in a syngeneic model. Following interaction with mesothelial cells, metastatic tumor cells contact fibroblasts. We find that omentum fibroblast expression of DDR2 promotes tumor cell invasion. Mechanistically, DDR2-expressing fibroblasts are more energetically active, such that DDR2 regulates glycolysis through AKT/SNAI1 leading to suppressed fructose-1,6-bisphosphatase and increased hexokinase activity, a key glycolytic enzyme. Upon inhibition of DDR2 we find decreased protein synthesis and secretion. Consequently, when DDR2 is inhibited in fibroblasts, there is reduction in secreted extracellular matrix proteins important for metastasis. Specifically, we find that fibroblast DDR2 inhibition leads to decreased secretion of the collagen crosslinker, LOXL2. Adding back LOXL2 to DDR2 deficient fibroblasts rescues the ability of tumor cells to invade. Overall, our results suggest that stromal cell expression of DDR2 is an important mediator of ovarian cancer metastasis. Citation Format: Angela Schab, Molly Greenwade, Elizabeth Stock, Elena Lomonosova, Kevin Cho, Whitney Grither, Hollie Noia, Daniel Wilke, Zainab Ibitoye, Mary Mullen, Andrea Hagemann, Ian Hagemann, Premal Thaker, Lindsay Kuroki, Carolyn McCourt, Dineo Khabele, Matthew Powell, David Mutch, Peinan Zhao, Leah Shriver, Gary Patti, Gregory Longmore, Katherine Fuh. Stromal cell DDR2 promotes ovarian cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A075.