Dissecting mechanisms of tumor initiation via immunomodulation

项目摘要/摘要 自2000年以来，胰腺癌的诊断率一直在上升，并对未来做出了预测。 认为到2030年，它将成为癌症死亡的第二大原因。此外，大多数患者死于 由于缺乏早期发现和早期干预，在确诊后一年内，这两者都限制了治疗 选择。胰腺导管腺癌(PDAC)是胰腺癌的主要形式，是胰腺癌的一种疾病 致癌克拉斯。关闭Kras突变体，包括KrasG12D或KrasG12V是治愈PDAC的关键。然而， 目前还没有已知的直接针对这两个突变体的抑制剂。PDAC起源于腺泡细胞 通过腺泡到导管的化生(ADM)过程。在获得致癌的Kras突变后，它 将腺泡细胞转化为导管样细胞，后者随后发展为癌细胞。因为1)激活 KRAS突变是PDAC生长和维持所必需的；2)ADM是PDAC的初始步骤 发展；3)PDAC中的KrasG12D和KrasG12V是不可用药的；4)PDAC患者也被诊断出来 后来，了解KrasG12D如何调节ADM和癌前病变的形成是重要的。收购 有关ADM过程及其监管的信息将为确定 用于早期检测的生物标志物和用于早期干预的药物靶点成功降低了死亡人数 PDAC的性能。我们确定CCL9是ADM和ADM胰腺腺泡中KrasG12D的一个新的下游靶点。 随后的Panin开发。到目前为止，对CCL9在生理和病理环境中的作用知之甚少。 CCL15的基因扩增是人类CCL9的同源基因，存在于人类PDAC中，是一种预测 生存时间更短。这项建议的目的是剖析KrasG12D/CCL9轴的机制和功能 PDAC启动与肿瘤发生。我们将以以下具体目标实现这一目标。1.至 阐明CCL9通过ADM诱导PDAC启动的机制；2.体内功能评价 CCL9在KrasG12D介导的PDAC启动中的作用。这些目标的成功实现将揭示新的功能 CCL9在PDAC的启动和发展中，为PDAC开发的早期事件添加了新的机械论见解， 并为CCL9的人类同源基因CCL15作为生物标志物之一奠定了必要的基础 针对早期发现和新的治疗策略，在临床上进行早期干预，对抗PDAC死亡。

Project Summary/Abstract Since the year 2000, pancreatic cancer diagnosis has been on the rise with future projections considering it to be the 2nd leading cause of cancer death by 2030. Furthermore, the majority of patients die within 1 year of diagnosis due to a lack of early detection and early intervention, both of which limit therapy options. Pancreatic ductal adenocarcinoma (PDAC) is the major form of pancreatic cancer and a disorder of oncogenic Kras. Turning off Kras mutants, including KrasG12D or KrasG12V is the key to curing PDAC. However, there are no known inhibitors which directly target these two mutants. PDAC originates from acinar cells through the acinar-to-ductal metaplasia (ADM) process. Upon acquisition of oncogenic Kras mutation, it converts acinar cells to duct-like cells, which subsequently develop into cancer cells. Because 1) activating Kras mutations are required for PDAC growth and maintenance; 2) ADM is the initial step of PDAC development; 3) KrasG12D and KrasG12V in PDAC are undruggable; and 4) PDAC patients are diagnosed too late, it is important to understand how KrasG12D regulates ADM and precancerous lesion formation. Acquiring information pertaining to the ADM process and its regulation will provide groundwork for the identification of biomarkers used for early detection, and drug targets for early intervention successfully reducing the death toll of PDAC. We identified CCL9 as a new downstream target of KrasG12D in pancreas acini of ADM and subsequent PanIN development. So far, little is known about CCL9 in physiological and pathological settings. Gene amplification of CCL15, a human orthologue of CCL9, is present in human PDAC and is a predictor of shorter survival. The goal of this proposal is to dissect the mechanisms and functions of KrasG12D/CCL9 axis on PDAC initiation and tumor development. We will accomplish this goal with the following specific aims. 1. To delineate the mechanisms of CCL9-induced PDAC initiation through ADM; 2. To evaluate the in vivo function of CCL9 in KrasG12D-mediated PDAC initiation. Successful completion of these aims will reveal new functions of CCL9 in PDAC initiation and growth, add new mechanistic insights into the early event of PDAC development, and establish the essential groundwork for CCL15, the human orthologue of CCL9, as one of the biomarkers for early detection and the new treatment strategies for early intervention in the clinic to fight PDAC death.