The action of DDR2 in cancer-associated fibroblasts promotes ovarian cancer metastasis through increased arginase-1 activity.

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SPECIFIC AIMS Ovarian cancer is the most lethal gynecological disease. 70-80% of ovarian cancer patients are diagnosed at stage III or IV when peritoneal metastasis has already occurred. The unique metastasis pattern in ovarian cancer involves the detachment of tumor cells, diffusion through the intraperitoneal space and attachment to the mesothelial layer lining the omentum and abdominal organs. Both increased collagen deposition and extracellular matrix (ECM) stiffening (due to altered collagen architecture) by stromal cells can create a pro- metastatic environment. Paracrine action of tumor growth-inducing molecules like polyamines can also promote metastasis. Identifying mechanisms that underlie collagen deposition and polyamine synthesis will allow better understanding of metastasis and thus further development of therapeutic interventions. One putative candidate for regulating metastasis is the fibrillar collagen-binding receptor tyrosine kinase Discoidin Domain Receptor-2 (DDR2). DDR2 expression is increased in the stroma of high grade serous ovarian cancer (HGSOC) patients and this increase is, alone, associated with shorter survival and worse response to therapy. We found that there were fewer intraperitoneal tumors when DDR2-expressing tumor cells were injected into the peritoneal cavity of syngeneic Ddr2-/- mice vs WT mice. To understand molecular reasons for this difference I performed targeted mRNA sequencing of tumors from Ddr2 WT and Ddr2-/- mice and found that expression of Arginase-1 was highly down-regulated in tumors from Ddr2-/- mice. Moreover, I found that shRNA depletion of DDR2 in WT ovarian omental cancer-associated fibroblasts also significantly decreased Arginase- 1 expression and activity. A major metabolic function of Arginase-I in cells is to promote arginine degradation into ornithine, which is a source of proline for collagen synthesis and polyamines that can impact cellular proliferation. Based upon these, and other, compelling preliminary data I propose to test the hypothesis: DDR2-regulated Arginase-1 expression in ovarian cancer omental CAFs promotes metastasis by impacting collagen production and ECM organization as well as polyamine synthesis. I will test this hypothesis by pursuing two specific aims: Aim 1: Determine the role of intracellular Arginase-1 in omental cancer-associated fibroblasts on collagen synthesis and architecture. Aim 2: Determine the role of intracellular Arginase-1 on polyamine-mediated tumor cell metastasis. These studies will uncover novel mechanisms by which DDR2 regulates arginase-1 in omental CAFs and how arginase-1 promotes metastasis through increased collagen deposition and polyamine synthesis. As DDR2 has been implicated in lung, pancreatic, and breast cancer, my findings may have broad implications in other cancers. This project will encourage my scientific growth as a physician scientist-in-training.