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/文摘