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.

项目总结/摘要 自2000年以来，胰腺癌的诊断一直在上升，未来的预测 到2030年，它将成为癌症死亡的第二大原因。此外，大多数患者死亡 由于缺乏早期发现和早期干预，在诊断后1年内，这两个因素都限制了治疗 选项.胰腺导管腺癌（PDAC）是胰腺癌的主要形式，并且是胰腺癌的一种病症。 致癌Kras。关闭Kras突变体，包括KrasG 12 D或KrasG 12 V，是治疗PDAC的关键。然而，在这方面， 没有已知的直接靶向这两种突变体的抑制剂。PDAC起源于腺泡细胞 通过腺泡-导管化生（ADM）过程。一旦获得致癌Kras突变， 将腺泡细胞转化为导管样细胞，随后发展为癌细胞。因为1）激活 PDAC的生长和维持需要Kras突变; 2）ADM是PDAC的起始步骤 PDAC中的KrasG 12 D和KrasG 12 V是不可治疗的;以及4）PDAC患者也被诊断为 最近，重要的是要了解KrasG 12 D如何调节ADM和癌前病变的形成。获取 有关行政管理过程及其管理的信息将为确定 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地减少了死亡人数 关于PDAC我们将CCL 9确定为ADM胰腺腺泡中KrasG 12 D的新下游靶点， 随后的PanIN发展。到目前为止，人们对CCL 9在生理和病理环境中的作用知之甚少。 CCL 15（CCL 9的人类直向同源物）的基因扩增存在于人类PDAC中，并且是PDAC的预测因子。 更短的生存。本研究的目的是探讨KrasG 12 D/CCL 9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实现这一目标。1.到 阐明CCL 9通过ADM诱导PDAC启动的机制; 2.评价体内功能 CCL 9在KrasG 12 D介导的PDAC启动中的作用。这些目标的成功完成将揭示新的功能， CCL 9在PDAC启动和生长中的作用，为PDAC发展的早期事件增加了新的机制见解， 并为CCL 9的人类直向同源物CCL 15作为生物标志物之一奠定了必要的基础 早期发现和新的治疗策略，在诊所早期干预，以打击PDAC死亡。