Targeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated Thrombosis

总结 胰腺导管腺癌（PDAC）是所有癌症中死亡率最高的癌症之一， 血栓栓塞并发症发生率最高。PDAC的促血栓形成潜力与以下因素直接相关： PDAC肿瘤细胞组织因子（TF）的高水平表达，可驱动体内旺盛的凝血酶活性， 循环和肿瘤微环境中。这项提议是基于侵袭性肿瘤 PDAC中的进展和血栓形成倾向通过关键的双向机制整合在一起， 肿瘤生长和促凝血潜能。初步数据表明，高水平的肿瘤细胞TF活性导致 凝血酶/PAR-1信号在PDAC肿瘤细胞和癌症相关的成纤维细胞（CAF），驱动局部 纤溶酶原激活（PA）系统组分尿激酶纤溶酶原激活剂（uPA）的产生， 受体（uPAR）。初步结果还表明，PA系统是一个中央播放器驱动的双向 PDAC肿瘤进展和静脉血栓栓塞并发症的机制。这些发现支持 中心假设，靶向PA系统成分将限制PDAC进展以及 同时矛盾地抑制PDAC相关血栓形成倾向。拟议的研究将直接 定义连接PAR-1/uPA/uPAR轴与PDAC肿瘤生长和侵袭的前馈机制 还将鉴定uPA/uPAR/纤溶酶原驱动PDAC中血栓形成倾向的反馈机制。 该联盟是止血，肿瘤生物学， 和生物工程。拟议的研究将采用多种创新方法，包括分析发展中国家的经济状况。 novo PDAC在独特的遗传修饰小鼠，一个尖端的3D仿生培养系统，新的 药理学工具和转化的患者来源的异种移植模型，以分析人肿瘤细胞， 咖啡馆。这一强大的专业知识和试剂集合将用于测试以下特定假设： (1)PAR-1驱动的PDAC肿瘤中uPA和uPAR的表达促进癌症进展，并驱动 通过介导肿瘤细胞相关TF促凝活性的释放，增加循环 促凝血活性;（2）肿瘤细胞内在的PAR-1活性通过诱导 uPA/uPAR，而CAFs的PAR-1信号转导驱动uPA/uPAR介导的组织重塑， 晚期PDAC;（3）单独或联合抗凝治疗的PA靶向治疗将 显著阻止PDAC肿瘤进展和相关的血栓形成倾向。拟议的研究 将为PAR-1/uPA/uPAR对PDAC病理生物学的贡献提供新的见解，阐明关键 PA系统与PDAC相关血栓形成倾向的耦合机制，并提供了重要的证据， 实验动物的主要数据和患者来源的材料，以便于将结果转化为 PDAC和癌症相关血栓形成的新疗法。

SUMMARY Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates of all cancers, and the highest rate of thromboembolic complications. The prothrombotic potential of PDAC has been directly linked to high-level expression of Tissue Factor (TF) by PDAC tumor cells that drives exuberant thrombin activity in circulation and in the tumor microenvironment. This proposal is based on evidence that aggressive tumor progression and thrombophilia in PDAC are integrally linked via key bi-directional mechanisms promoting tumor growth and procoagulant potential. Preliminary data suggests that high-level tumor cell TF activity leads to thrombin/PAR-1 signaling in PDAC tumor cells and cancer-associated fibroblasts (CAFs), driving local production of the plasminogen activation (PA) system components, urokinase plasminogen activator (uPA) and receptor (uPAR). Initial results also indicate that the PA system is a central player driving the bi-directional mechanisms of PDAC tumor progression and venous thromboembolic complications. These findings support the central hypothesis that targeting PA system components will limit PDAC progression as well as simultaneously and paradoxically suppress PDAC-associated thrombophilia. The proposed studies will directly define the feed forward mechanisms linking the PAR-1/uPA/uPAR axis to PDAC tumor growth and invasion and will also identify the feedback mechanisms by which uPA/uPAR/plasminogen drive thrombophilia in PDAC. This consortium is a collaboration of experts in the basic and clinical sciences of hemostasis, tumor biology, and bioengineering. The proposed studies will use multiple innovative approaches, including analysis of de novo PDAC in unique genetically-modified mice, a cutting-edge 3D biomimetic culture system, novel pharmacological tools, and translational patient-derived xenograft models to analyze human tumor cells and CAFs. This powerful collection of expertise and reagents will be used to test the following specific hypotheses: (1) PAR-1-driven expression of uPA and uPAR in PDAC tumors promotes cancer progression, and drives thrombosis by mediating the release of tumor-cell associated TF procoagulant activity that increases circulating procoagulant activity; (2) tumor cell-intrinsic PAR-1 activity supports PDAC invasion through induction of uPA/uPAR, while PAR-1 signaling by CAFs drives uPA/uPAR-mediated tissue remodeling associated with advanced PDAC; and (3) therapies targeting PA either alone or in combination with anticoagulation will significantly impede both PDAC tumor progression and the associated thrombophilia. The proposed studies will provide novel insights into the contribution of PAR-1/uPA/uPAR to PDAC pathobiology, illuminate key mechanisms coupling the PA system to PDAC-associated thrombophilia, and provide essential proof-of- principle data in experimental animals and with patient-derived material to facilitate translation of findings into new treatments for PDAC and cancer-associated thrombosis.