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.

项目总结/摘要 胰腺导管腺癌（PDA）预后很差。了解导致 发展和发展的PDA，以确定新的干预方法是最大的 预防和治疗的希望。动物模型表明，胰腺癌的发展是 由两个事件驱动，KRas中致癌突变的获得和胰腺炎症。我们 以前的研究表明，致癌KRas上调可溶性ICAM 1（sICAM 1）， 作为炎性巨噬细胞（M1）的化学引诱物，启动胰腺病变的形成。我们也 已经表明，胰腺病变，通过释放IL-13，可以与M1巨噬细胞群串话， 以诱导其极化为促进肿瘤的交替激活表型（M2）。这项建议 侧重于了解巨噬细胞如何被癌前病变吸引的机制， 也是关于如何防止它们转化为肿瘤相关的巨噬细胞。我们假设 KRas驱动的ICAM-1的表达是巨噬细胞群体的调节剂，其靶向可以具有 对胰腺癌的发展和进展有重要影响。为了验证这一点，我们将：确定如何 致癌KRas导致形成可溶形式的ICAM 1（特异性目的1）;确定MMP 3的作用 和ICAM 1在吸引炎性巨噬细胞中的作用（特异性目的2）; MMP 3与sICAM 1的产生、巨噬细胞的化学吸引和PDA的发展 （具体目标3）;并单独测试ICAM 1靶向策略，以及与当前化疗联合使用 或肿瘤微环境的调节剂（具体目标4）。成功完成我们的项目将 证明了KRas诱导的ICAM 1表达和加工对发育的重要性， 胰腺癌的进展，但也导致新的策略，以保持巨噬细胞缺席，从而停止 结缔组织增生、病变进展和转移。