Thrombin-dependent mechanisms of pancreatic ductal adenocarcinoma disease

项目总结 胰腺导管腺癌(PDAC)是所有癌症中死亡率最高的，正在迅速成为 这是美国癌症死亡的第二大原因，据估计，医疗保健系统的成本为2.4美元 每年10亿美元。患有PDAC的患者的5年存活率为7%，而 患有转移性疾病的个体。不幸的是，在改变患者预后方面进展甚微。 在过去的40年里，强调了需要创新的方法来定义 影响PDAC的发展。PDAC可在获得激活的外分泌上皮细胞中启动 KRAS原癌基因突变，导致细胞向胰腺上皮内瘤变转变 (Panin)可进展为PDAC的病变。对KRAS活性的关键转录反应增加 凝血系统的生理激活物组织因子(TF)的表达。TF调停 凝血酶原转化为活性蛋白酶凝血酶，进而促进体内广泛的纤维蛋白沉积 肿瘤微环境(TME)与激活G蛋白偶联的蛋白酶激活受体(PARs)的关系 靶细胞，包括PDAC肿瘤细胞、肿瘤相关巨噬细胞(TAM)和癌症相关细胞 成纤维细胞(CAF)。科学前提是基于胰腺癌和癌症之间的已知关系。 高凝血系统的活性，但它的独特之处在于它将定义新发现的 TME中的特定凝血因子通过串扰促进PDAC的发病。我们的中央 假说是凝血酶驱动早期PAIN的发展以及晚期PDAC肿瘤的生长和 TME纤维蛋白基质沉积和PAR-1信号转导机制的研究 TME细胞促进PDAC疾病的前馈通路。这一假设将通过使用 结合了独特的基因工程小鼠模型、尖端药物试剂和 患者来源的PDAC肿瘤细胞追求三个特定目标--(1)确定凝血酶-纤维蛋白轴 有助于早期Panin的发展和晚期PDAC肿瘤的生长和转移；(2)确定 肿瘤细胞、TAM和CAF上凝血酶受体PAR-1信号转导的个别机制 加重PDAC发病机制的不同方面；以及(3)确定药理纤维蛋白的疗效 和PAR-1抑制在阻止已建立的小鼠和人类患者来源的PDAC进展中的作用 异种移植瘤。这些研究具有重要意义，因为它们将(I)第一个确定 凝血酶在PDAC疾病中的作用；(Ii)确定凝血酶依赖的PDAC疾病的具体机制 进展；以及(Iii)提供使用特定最先进的抑制剂靶向PDAC肿瘤的新机会 纤维蛋白基质和PAR-1信号通路。所取得的发现将极大地促进人们对 的潜在机制，并有望突出新的治疗机会 开发改进的治疗方案--这是一个对患者结局有最大益处的长期目标。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all cancers, is rapidly becoming the second leading cause of cancer deaths in the U.S., and is estimated to cost the health care system $2.4 billion each year. Patients with PDAC have a 5-year survival rate of 7% and that number drops to 2% for individuals with metastatic disease. Unfortunately, there has been little progress in shifting patient outcome over the past 40 years, highlighting the need for innovative approaches to define the molecular pathways that influence PDAC development. PDAC can be initiated in exocrine epithelial cells that acquire an activating mutation in the KRAS protooncogene, causing the cells to transition to pancreatic intraepithelial neoplasia (PanIN) lesions that can progress into PDAC. A key transcriptional response to KRAS activity is increased expression of the physiological activator of the coagulation system, Tissue Factor (TF). TF mediates conversion of prothrombin to the active protease thrombin that in turn promotes extensive fibrin deposits within the tumor microenvironment (TME) and activates G-protein coupled protease-activated receptors (PARs) on target cells, including PDAC tumor cells, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). The scientific premise is based on a known relationship between pancreatic cancer and high-level blood coagulation system activity, but is unique in that it will define newly discovered mechanisms of crosstalk by which specific coagulation factors in the TME promote PDAC pathogenesis. Our central hypothesis is that thrombin drives early PanIN development as well as advanced PDAC tumor growth and metastasis by mechanisms linked to both fibrin matrix deposition in the TME and PAR-1 signaling on tumor and TME cells promoting a feed forward pathway of PDAC disease. This hypothesis will be tested by utilizing a combination of unique genetically engineered mouse models, cutting-edge pharmaceutical reagents, and patient-derived PDAC tumor cells to pursue three Specific Aims - (1) determine how the thrombin-fibrin axis contributes to early PanIN development and late stage PDAC tumor growth and metastasis; (2) determine the individual mechanisms by which thrombin receptor PAR-1 signaling on tumor cells, TAMs and CAFs exacerbates distinct aspects of PDAC pathogenesis; and (3) determine the efficacy of pharmacological fibrin and PAR-1 inhibition in halting the progression of established mouse PDAC and human patient-derived xenograft tumors. These studies are significant because they will (i) be the first to define the impact of thrombin throughout PDAC disease; (ii) identify specific mechanisms of thrombin-dependent PDAC disease progression; and (iii) provide novel opportunities to target PDAC tumors using specific state-of-the-art inhibitors of fibrin matrix and PAR-1 signaling pathways. The discoveries made will greatly advance the understanding of mechanisms underlying PDAC disease and are expected to highlight novel therapeutic opportunities for developing improved treatment options - a long-term goal with the greatest benefit to patient outcome.