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.

项目摘要/摘要 胰腺导管腺癌（PDA）带有令人沮丧的预后。了解领导的机制 为了确定新颖的干预方法，PDA的发展和发展是最大的 希望预防和治疗。动物模型表明胰腺癌的发展是 在两个事件的驱动下，在KRAS和胰腺炎症中获得了致癌突变。我们的 先前的工作表明，致癌性Kras上调了一种可溶性的ICAM1（SICAM1），该形式起作用 作为炎症性巨噬细胞（M1）的趋化因子，以启动胰腺病变的形成。我们也是 已经表明，通过释放IL-13，胰腺病变可以与M1巨噬细胞串扰 为了诱导其极化为促进肿瘤的替代激活的表型（M2）。这个建议 专注于理解如何被癌性病变吸引巨噬细胞的机制，但 还可以预防它们转化为肿瘤相关的巨噬细胞。我们的假设是 ICAM-1的KRAS驱动表达是巨噬细胞种群的调节剂，其靶向可以具有 对胰腺癌发育和进展的主要影响。为了测试这一点，我们将：确定如何 致癌性KRA会导致形成ICAM1的可溶性形式（特定目标1）；确定mmp3的作用 和ICAM1吸引炎症性巨噬细胞（特定目标2）；确定体内功能 MMP3关于SICAM1的产生，巨噬细胞的趋化和PDA的发展 （特定目标3）;并仅测试ICAM1靶向策略，并与当前的化学疗法结合 或肿瘤微环境的调节剂（特定目标4）。成功完成我们的项目将 证明KRAS诱导的ICAM1表达和处理对开发的重要性 胰腺癌的进展，但也导致了保持巨噬细胞不存在的新策略，从而停止了 脱木质，病变的进展和转移。