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.

项目概要/摘要 自2000年以来，胰腺癌的诊断率一直在上升，并且对未来的预测 到 2030 年，它将成为癌症死亡的第二大原因。此外，大多数患者会死亡 由于缺乏早期发现和早期干预，诊断后一年内，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，也是一种胰腺癌疾病 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， 没有已知的抑制剂直接针对这两种突变体。 PDAC起源于腺泡细胞 通过腺泡到导管化生（ADM）过程。在获得致癌性 Kras 突变后， 将腺泡细胞转化为导管样细胞，随后发育成癌细胞。因为1）激活 PDAC 生长和维持需要 Kras 突变； 2）ADM是PDAC的第一步 发展; 3）PDAC中的KrasG12D和KrasG12V不可成药； 4) PDAC 患者也被诊断出来 后期，了解 KrasG12D 如何调节 ADM 和癌前病变形成非常重要。收购 有关 ADM 流程及其监管的信息将为识别 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 的 PDAC。我们确定 CCL9 是 ADM 胰腺腺泡中 KrasG12D 的新下游靶标 随后的 PanIN 开发。迄今为止，人们对 CCL9 在生理和病理环境中的作用知之甚少。 CCL15（CCL9 的人类直系同源物）的基因扩增存在于人类 PDAC 中，并且是 CCL9 的预测因子 生存期较短。该提案的目标是剖析 KrasG12D/CCL9 轴的机制和功能 PDAC 启动和肿瘤发展。我们将通过以下具体目标来实现这一目标。 1. 至 描述 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。这些目标的成功完成将揭示出新的功能 CCL9参与PDAC的启动和生长，为PDAC发展的早期事件添加新的机制见解， 并为 CCL15（CCL9 的人类直系同源物）作为生物标志物之一奠定重要基础 早期检测和临床早期干预的新治疗策略，以对抗 PDAC 死亡。