Abstract A47: miR-30c: a TGF beta-regulated miRNA that coordinates vascular-directed fibrinolysis and tumor angiogenesis

Tumor-associated endothelial cells (TECs) are dysfunctional and leak fibrin which is resolved (fibrinolysis) and replaced with collagen in a process that closely resembles wound healing. Because degraded perivascular fibrin also promotes angiogenesis and creates scaffolds for invasive cancer cells, vascular-directed fibrinolysis in solid tumors is a fundamental spark during tumor progression. Using a miRNA screen of freshly isolated TECs, we identified a TGF beta-regulated miRNA that controls vascular-mediated fibrinolysis in tumors. miR-30c is increased in TECs relative to normal endothelial cells (NECs) whereas its target PAI-1 (a fibrinolysis inhibitor) is strikingly decreased. TECs secrete less PAI-1 and they rapidly degrade and migrate through fibrin scaffolds resulting in uncoordinated vessel sprouting. However, TGF beta and miR-30c antagomiRs reduce miR-30c expression which re-instates PAI-1 secretion, diminishes vascular-specific fibrinolysis, and “normalizes” TEC sprouting. miR-30c antagomiRs coupled to vascular-tropic nanoparticles reduce TEC migration in fibrin and enforce vascular expression of PAI-1 in vitro and in vivo. Thus, vascular-specific expression of miR-30c in tumors may be manipulated in vivo using this nanoparticle-based strategy. We also show that TGF beta promotes the export of miR-30c in extracellular vesicles (EVs) which are received by recipient stromal cells. TGF beta-mediated extravascular mobilization of miR-30c may down regulate PAI-1 expression in nearby stromal cells or cancer cells thereby programing fibrinolysis in these non-vascular recipients. Taken together, we propose an axis between TGF beta, miR-30c, and PAI-1 in TECs controls the rate of perivascular fibrinolysis and is therefore an important effector of tumor emergence. Citation Format: James V. McCann, Lin Xiao, Omar Khan, Piotr Kowalski, Salma Azam, Chad V. Pecot, Daniel G. Anderson, Andrew C. Dudley. miR-30c: a TGF beta-regulated miRNA that coordinates vascular-directed fibrinolysis and tumor angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A47.