Dissecting mechanisms of tumor initiation via immunomodulation

通过免疫调节剖析肿瘤发生机制

• 批准号: 10569591
• 负责人: Geou-Yarh Liou
• 金额: $ 34.65万
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569591
• 关键词: 3-Dimensional; Acceleration; Acinar Cell; Acinus organ component; Animal Model; Back; CCL15 gene; Cancer Etiology; Cells; Cessation of life; Clinic; Death Rate; Development; Diagnosis; Digit structure; Disease; Drug Targeting; Duct (organ) structure; Early Diagnosis; Early Intervention; Event; Future; Gene Amplification; Goals; Growth; Human; Incidence; KRAS oncogenesis; KRASG12D; Knock-out; Lesion; Location; Longevity; Macrophage; Maintenance; Malignant neoplasm of pancreas; Matrix Metalloproteinases; Mediating; Metaplasia; Mutation; Operative Surgical Procedures; Organ; Organoids; Outcome Study; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathologic; Patients; Physiological; Process; RANTES; Reactive Oxygen Species; Regulation; Reporting; Signal Transduction; Survival Rate; Symptoms; System; TNF gene; Transgenic Mice; Unresectable; antagonist; biomarker identification; cancer cell; cancer diagnosis; chemotherapy; early detection biomarkers; fighting; immunoregulation; in vivo; inhibitor; insight; mortality; mouse model; mutant; neutralizing antibody; novel therapeutic intervention; pancreatic cancer patients; premalignant; receptor; tumor; tumor initiation

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.

项目摘要/摘要 自2000年以来，随着未来预测，胰腺癌的诊断一直在上升 考虑到到2030年是癌症死亡的第二大原因。此外，大多数患者死亡 由于缺乏早期检测和早期干预，在诊断后的1年内，这两者都限制了治疗 选项。胰腺导管腺癌（PDAC）是胰腺癌的主要形式，是一种疾病 致癌kras。关闭包括Krasg12d或Krasg12v在内的KRAS突变体是固化PDAC的关键。然而， 没有已知的抑制剂直接靶向这两个突变体。 PDAC起源于腺泡细胞 通过腺泡到外向的化生（ADM）过程。收购致癌性KRAS突变后 将腺泡细胞转换为管道样细胞，后来发展为癌细胞。因为1）激活 PDAC生长和维护需要KRAS突变； 2）ADM是PDAC的第一步 发展; 3）PDAC中的krasg12d和krasg12v是不可能的； 4）PDAC患者也被诊断出 迟到，重要的是要了解Krasg12d如何调节ADM和癌性病变的形成。获取 与ADM程序及其法规有关的信息将为识别提供基础 用于早期检测的生物标志物和用于早期干预的药物靶标成功减少了死亡人数 PDAC。我们将CCL9确定为ADM胰腺Acini的Krasg12d的新下游目标 随后的Panin Development。到目前为止，在生理和病理环境中CCL9知之甚少。 CCL15的基因扩增是CCL9的人类直系同源物，存在于人类PDAC中，是预测指标 较短的生存。该提案的目的是剖析KRASG12D/CCL9轴的机制和功能 PDAC启动和肿瘤的发展。我们将以以下特定目标来实现这一目标。 1 描述了通过ADM的CCL9诱导的PDAC启动的机制； 2。评估体内功能 KRASG12D介导的PDAC启动中的CCL9。这些目标的成功完成将揭示 CCL9在PDAC启动和增长中，在PDAC开发的早期事件中添加新的机械见解， 并建立CCL15的基本基础，即CCL9的人类直系同源物作为生物标志物之一 为了早期检测和在诊所早期干预以与PDAC死亡作斗争的新治疗策略。