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; 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）的死亡率最高，是所有癌症的死亡率之一，并且是 血栓栓塞并发症的最高率。 PDAC的促血栓性潜力已直接与 PDAC肿瘤细胞对组织因子（TF）的高级表达 循环和肿瘤微环境。该提议基于证据表明侵略性肿瘤 PDAC中的进展和血栓形成通过促进的钥匙双向机制在PDAC中的积极联系 肿瘤的生长和凝聚力。初步数据表明高级肿瘤细胞TF活性导致 在PDAC肿瘤细胞和与癌症相关的成纤维细胞（CAF）中进行凝血酶/PAR-1信号传导，驱动局部 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）。初始结果还表明，PA系统是驾驶双向的中心参与者 PDAC肿瘤进展和静脉血栓栓塞并发症的机制。这些发现支持 靶向PA系统组件将限制PDAC进展以及 同时且矛盾地抑制与PDAC相关的血栓形成。拟议的研究将直接 定义将PAR-1/UPA/UPAR轴与PDAC肿瘤生长和入侵联系起来的饲料前馈机制 并将确定PDAC中UPA/UPA/纤溶酶驱动血栓形成的反馈机制。 该财团是止血，肿瘤生物学，肿瘤生物学基础和临床科学专家的合作 和生物工程。拟议的研究将使用多种创新方法，包括对DE的分析 独特的遗传改性小鼠的Novo PDAC，一种尖端的3D仿生培养系统，新型 药理学工具和转化的患者衍生的异种移植模型，以分析人类肿瘤细胞和 咖啡馆。这种强大的专业知识和试剂集合将用于检验以下特定假设： （1）PDAC肿瘤中UPA和UPAR的PAR-1驱动表达促进癌症的进展，并驱动 通过介导肿瘤细胞相关的TF促凝活性的释放来增加循环的血栓形成 Procagulant活动； （2）通过诱导 UPA/UPAR，而CAFS的PAR-1信令则驱动UPA/UPAR介导的组织重塑与 高级PDAC; （3）靶向PA的疗法单独或与抗凝作用结合使用 显着阻碍PDAC肿瘤进展和相关的血栓形成。提出的研究 将为PAR-1/UPA/UPAR对PDAC病理生物学的贡献提供新的见解 将PA系统耦合到PDAC相关的血栓形成的机制，并提供必要的证明 实验动物和患者衍生的材料中的主要数据，以促进发现结果 PDAC和癌症相关血栓形成的新治疗方法。