Role of ICAM1 in development and progression of pancreatic cancer

ICAM1在胰腺癌发生和进展中的作用

• 批准号: 10560622
• 负责人: Peter Storz
• 金额: $ 35.08万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560622
• 关键词: Acinar Cell; Advanced Malignant Neoplasm; Affect; Animal Model; Cells; Chemotactic Factors; Combined Modality Therapy; Data; Development; Event; Generations; Goals; ICAM1 gene; Immunotherapy; Infiltration; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interleukin-13; Intervention; KPC model; KRAS oncogenesis; KRAS2 gene; KRASG12D; Knock-out; Knockout Mice; Lesion; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Matrix Metalloproteinases; Mediating; Messenger RNA; Methods; Mutation; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patient-Focused Outcomes; Patients; Phenotype; Population; Prevention; Process; Production; Prognosis; Prognostic Factor; Protein Isoforms; Resected; Role; Signal Pathway; Stromelysin 1; Survival Rate; Testing; Therapeutic; Tumor Promotion; Tumor-associated macrophages; Work; chemotherapy; in vivo; insight; neoplastic cell; neutralizing antibody; novel; novel strategies; novel therapeutic intervention; pancreas development; pre-clinical; premalignant; prevent; receptor; standard of care; transgene expression; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Understanding the mechanisms that lead to the development and progression of PDA in order to identify novel methods of intervention is the greatest hope for prevention and treatment. Animal models have shown that the development of pancreatic cancer is driven by two events, the acquisition of an oncogenic mutation in KRas and pancreatic inflammation. Our previous work demonstrated that oncogenic KRas upregulates a soluble form of ICAM1 (sICAM1), which acts as chemoattractant for inflammatory macrophages (M1) to initiate the formation of pancreatic lesions. We also have shown that pancreatic lesions, by releasing IL-13, can crosstalk with M1 macrophage populations in order to induce their polarization to an alternatively-activated phenotype (M2) that is tumor promoting. This proposal focusses on understanding the mechanism of how macrophages are attracted by precancerous lesions, but also on how their conversion into tumor-associated macrophages can be prevented. It is our hypothesis that KRas-driven expression of ICAM-1 is a regulator of macrophage populations and its targeting can have major effects on development and progression of pancreatic cancer. To test this we will: determine how oncogenic KRas leads to formation of a soluble form of ICAM1 (Specific Aim 1); determine the roles of MMP3 and ICAM1 in attracting inflammatory macrophages (Specific Aim 2); To determine the in vivo function of MMP3 with respect to production of sICAM1, chemoattraction of macrophages and development of PDA (Specific Aim 3); and test an ICAM1 targeting strategy alone, and in combination with current chemotherapy or modulators of the tumor microenvironment (Specific Aim 4). Successful completion of our project will demonstrate the importance of KRas-induced expression and processing of ICAM1 for the development and progression of pancreatic cancer, but also lead to novel strategies to keep macrophages absent, and thus halt desmoplasia, lesion progression and metastasis.

项目概要/摘要 胰腺导管腺癌（PDA）的预后很差。了解导致的机制 对PDA的发展和进展以确定新的干预方法是最重要的 希望得到预防和治疗。动物模型表明胰腺癌的发生与发展有关 由两个事件驱动，KRas 中致癌突变的获得和胰腺炎症。我们的 先前的工作表明，致癌 KRas 上调可溶形式的 ICAM1 (sICAM1)，其作用 作为炎症巨噬细胞 (M1) 的化学引诱剂，引发胰腺病变的形成。我们也 研究表明，胰腺病变可通过释放 IL-13 与 M1 巨噬细胞群进行交互作用 诱导它们极化为促进肿瘤生长的替代激活表型（M2）。这个提议 重点在于了解巨噬细胞如何被癌前病变吸引的机制，但是 还涉及如何防止它们转化为肿瘤相关巨噬细胞。我们的假设是 KRas 驱动的 ICAM-1 表达是巨噬细胞群的调节因子，其靶向可以具有 对胰腺癌的发生和进展有重大影响。为了测试这一点，我们将： 确定如何 致癌 KRas 导致形成可溶形式的 ICAM1（具体目标 1）；确定 MMP3 的作用 ICAM1 吸引炎症巨噬细胞（具体目标 2）；确定体内功能 MMP3 与 sICAM1 的产生、巨噬细胞的化学吸引和 PDA 的发育有关 （具体目标 3）；并单独测试 ICAM1 靶向策略，并与当前化疗相结合 或肿瘤微环境的调节剂（具体目标 4）。我们的项目的成功完成将 证明 KRas 诱导的 ICAM1 表达和加工对于发育和发育的重要性 胰腺癌的进展，但也导致了保持巨噬细胞缺失的新策略，从而阻止 结缔组织增生、病变进展和转移。