Role of ICAM1 in development and progression of pancreatic cancer

项目摘要/摘要 胰腺导管腺癌(PDA)预后很差。了解导致 对PDA的发展和进步来说，找出新的干预方法是最大的 希望能预防和治疗。动物模型已经表明，胰腺癌的发展是 在两个事件的推动下，KRAS的致癌突变的获得和胰腺炎症。我们的 以前的工作表明，致癌的KRAS上调了可溶性形式的ICAM1(SICAM1)，它起作用 作为炎性巨噬细胞(M1)的趋化剂，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，可以顺序地与M1巨噬细胞群串扰 诱导它们的极化到交替激活的表型(M2)，即促进肿瘤。这项建议 专注于了解巨噬细胞如何被癌前病变吸引的机制，但 以及如何防止它们转化为肿瘤相关的巨噬细胞。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，其靶向可能具有 对胰腺癌发生发展的主要影响。为了测试这一点，我们将：确定如何 致癌KRAS导致可溶性ICAM1的形成(特异靶1)；确定MMP3的作用 和ICAM1在吸引炎性巨噬细胞中的作用(特异性靶点2)；确定其体内功能 MMP3与sICAM-1的产生、巨噬细胞的趋化及PDA的发展 (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(特定目标4)。我们项目的成功完成将 证明KRAS诱导ICAM1的表达和加工对发育和发育的重要性 胰腺癌的进展，但也导致新的策略，使巨噬细胞不存在，从而阻止 结缔组织增生、病变进展和转移。

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.