Investigating tumor-mesothelial cell interactions during ovarian cancer metastasis

项目总结

PROJECT SUMMARY Ovarian cancer is the leading cause of gynecological cancer-related deaths. The propensity for metastasis is a driving factor for the poor outcomes associated with this disease, but there is yet to be an effective therapy targeting metastasis. Ovarian cancer frequently metastasizes to the peritoneal cavity, where it attaches to mesothelial cells surrounding the organs of the peritoneum, displaces this layer, and invades into the underlying stroma. Mesothelial cells become active participants in this process, depositing and remodeling extracellular matrix to which tumor cells can adhere. Mesothelial cells therefore offer a promising therapeutic target. However, the manner in which they become permissive to metastasis is not yet fully understood. Preliminary work from our lab suggests that mesothelial cell expression of the receptor tyrosine kinase Discoidin Domain Receptor 2 (DDR2) promotes metastasis. After injecting mouse ovarian cancer cells into mice, mice in which Ddr2 is globally knocked out demonstrate significantly decreased tumor burden compared to wild type mice. Further, in vitro preliminary data suggests that inhibition of mesothelial cell DDR2 decreases tumor cell clearance. Additionally, inhibition of mesothelial DDR2 decreases protein expression of the mesenchymal transcription factor SNAI1, and transcription and secretion of mesenchymal associated protein MMP-2, even in the absence of collagen - the ligand of DDR2. This proposal aims to 1) determine the mechanisms by which mesothelial DDR2 expression contributes to ovarian cancer metastasis and 2) define the effects of collagen-dependent vs. collagen-independent DDR2 signaling in mesothelial cells during the steps of metastasis. Through testing an in vivo mesothelial-specific Ddr2 knockout mouse that I have generated (Aim 1) and identifying collagen-independent mechanisms by which DDR2 expression contributes to metastasis (Aim 2) this proposal will test the hypothesis that DDR2 acting in mesothelial cells creates an environment permissive to ovarian cancer metastasis in the peritoneal cavity. In the long run, this proposal can contribute to the development of new therapeutics that improve outcomes, delay metastases, and prolong life in patients suffering from ovarian cancer. In addition to expanding our understanding of the mechanisms by which ovarian cancer metastasizes, this proposal will foster the development of new skills to lay the foundation for a lifelong career in the study of cancer biology.