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

靶向纤溶酶原激活系统以限制胰腺癌进展和相关血栓形成

• 批准号: 10458582
• 负责人: MATTHEW J FLICK
• 金额: $ 83.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458582
• 关键词: 3-Dimensional; Acute; Animals; Anticoagulation; Antifibrinolytic Agents; Automobile Driving; Basic Science; Biomedical Engineering; Biomimetics; Blood Circulation; Blood coagulation; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; Clinical Sciences; Coagulation Process; Collaborations; Collection; Coupled; Coupling; Data; Development; Disease; Drops; Event; Feedback; Fibroblasts; Fostering; Frequencies; GTP-Binding Proteins; Goals; Growth; Health Care Costs; Healthcare Systems; Hemostatic function; High-Risk Cancer; Human; Individual; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; Nature; Neoplasm Circulating Cells; PAR-1 Receptor; Pancreatic Ductal Adenocarcinoma; Pathologic; Pathway interactions; Patients; Pharmacology; Plasminogen; Play; Production; Proteins; Public Health; Reagent; Research; Risk; Role; Signal Transduction; Survival Rate; System; Testing; Thrombin; Thrombophilia; Thromboplastin; Thrombosis; Thrombus; Tissues; Translations; Tumor Biology; Tumor Cell Invasion; Tumor Tissue; Tumor-Derived; Urokinase; Urokinase Plasminogen Activator Receptor; Venous; base; cancer complication; improved; in vivo; innovation; insight; mortality; mutant; neoplastic cell; novel; patient derived xenograft model; patient prognosis; plasminogen receptor; programs; receptor; receptor expression; receptor function; targeted treatment; thrombotic; thrombotic complications; tool; tumor; tumor growth; tumor microenvironment; tumor progression

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.

概括 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 的促血栓潜力与 PDAC 肿瘤细胞高水平表达组织因子 (TF)，驱动凝血酶活性旺盛 循环和肿瘤微环境中。该提议基于以下证据：侵袭性肿瘤 PDAC 的进展和血栓形成倾向通过关键的双向机制紧密相连 肿瘤生长和促凝血潜力。初步数据表明，高水平的肿瘤细胞 TF 活性导致 PDAC 肿瘤细胞和癌症相关成纤维细胞 (CAF) 中的凝血酶/PAR-1 信号传导，驱动局部 产生纤溶酶原激活 (PA) 系统成分、尿激酶纤溶酶原激活剂 (uPA) 和 受体（uPAR）。初步结果还表明，PA 系统是驱动双向广播的核心角色。 PDAC肿瘤进展和静脉血栓栓塞并发症的机制。这些发现支持 中心假设是针对 PA 系统组件将限制 PDAC 进展以及 同时矛盾地抑制 PDAC 相关的血栓形成倾向。拟议的研究将直接 定义将 PAR-1/uPA/uPAR 轴与 PDAC 肿瘤生长和侵袭联系起来的前馈机制 还将确定 uPA/uPAR/纤溶酶原驱动 PDAC 血栓形成倾向的反馈机制。 该联盟由止血、肿瘤生物学、基础科学和临床科学领域的专家组成。 和生物工程。拟议的研究将使用多种创新方法，包括对 de novo PDAC 在独特的转基因小鼠中，一种尖端的 3D 仿生培养系统，新颖 药理学工具和转化患者来源的异种移植模型来分析人类肿瘤细胞和 CAF。这一强大的专业知识和试剂集合将用于测试以下具体假设： (1) PDAC肿瘤中PAR-1驱动的uPA和uPAR表达促进癌症进展，并驱动 通过介导肿瘤细胞相关 TF 促凝血活性的释放来增加循环，从而形成血栓 促凝血活性； (2) 肿瘤细胞固有的 PAR-1 活性通过诱导 uPA/uPAR，而 CAF 的 PAR-1 信号驱动 uPA/uPAR 介导的组织重塑 先进的PDAC； (3) 单独针对 PA 的治疗或与抗凝药物联合治疗将 显着阻止 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 病理学的贡献提供新颖的见解，阐明关键 PA 系统与 PDAC 相关的血栓形成倾向的耦合机制，并提供必要的证据- 实验动物的主要数据和患者来源的材料，以促进将发现转化为 PDAC 和癌症相关血栓形成的新疗法。