Mechanisms & Therapeutic Targeting of the Microenvironment in Pancreatic Cancer

项目3将使用先前开发的多阶段胰腺癌发生的小鼠模型， 项目1同时分析，以研究肿瘤微环境及其组成细胞 类型作为INK 4a/Arf、p53和/或SMAD 4肿瘤抑制因子的损失以及肿瘤抑制因子的活性的函数。 PI 3激酶途径，所有这些都在突变激活的KRAS信号传导的背景下。微环境 待评估的参数包括：血管生成和血管系统的特征; 周细胞与肿瘤血管系统的关系; 血管;浸润（肿瘤增强）白细胞的丰度和类型以及 它们产生的基质降解酶;以及成纤维基质细胞的特征。 一个中心目标是测试假设，即肿瘤的血管生成表型和其他特征， PanIN和PDAC的微环境受到特定肿瘤抑制因子的缺失的差异调节。 这些基因是这种疾病的标志将与项目2合作实现的一个辅助目标是： 为了确定癌细胞中KRAS信号通过PIS激酶网络的重要性， 异常的肿瘤微环境人体肿瘤活检标本的实验病理学分析 Core将评估小鼠中鉴定的遗传和表型参数的相关性。 将建立肿瘤阶段特异性临床前试验设计，并用于测试创新的 化疗方案，靶向抗血管生成疗法，以及可能指导未来 人体临床试验与成像核心的联合研究将开发非侵入性可视化探针 微环境的参数，以监测病变进展和对治疗的反应。 项目4确定的起源细胞/胰腺癌干细胞的生物标志物将用于评估 对治疗的特异性反应和在复发/进展中的作用。. 这些研究在新生胰腺癌的工程小鼠模型中进行，将表征 前所未有的细节异常病变微环境及其调控的基因突变， 多阶段进展，并开始基于知识的临床前治疗试验，有可能揭示 这些策略可以转化为人类疾病的改进治疗方法。

Project 3 will use mouse models of multistage pancreatic carcinogenesis previously developed and concurrently analyzed by Project 1 to investigate the neoplastic microenvironment and its constituent cell types as functions of losses in the INK4a/Arf, p53, and/or SMAD4 tumor suppressors, and of activity of the PI3 Kinase pathway, all in the context of mutationally activated KRAS signaling. Microenvironmental parameters to be assessed include: angiogenesis and the character of the blood vasculature; the association of pericytes with the tumor vasculature; lymphangiogenesis and the morphology of the lymphatic vasculature; the abundance and types of infiltrating (tumor-enhancing) leucocytes and expression/activity of the matrix-degrading enzymes they produce; and the characteristics of the fibroblastic stromal cells. A central goal is to test the hypothesis that the angiogenic phenotype and other features of the neoplastic microenvironment of PanIN and PDAC are differentially regulated by the loss of particular tumor suppressor genes that are signatures of this disease. An ancillary goal, to be pursued in collaboration with Project 2, is to determine the importance of KRAS signaling via the PIS kinase network in the cancer cells for induction of the aberrant tumor microenvironment. Analysis of human tumor biopsies with the Experimental Pathology Core will assess the correlation of genetic and phenotypic parameters identified in the mouse. Neoplastic stage-specific preclinical trial designs will be established and used to test innovative chemotherapeutic regimens, targeted antiangiogenic therapies, and combinations that might guide future human clinical trials. Joint studies with the Imaging Core will develop probes that non-invasively visualize parameters of the microenvironment, both to monitor lesional progression, and responses to therapy. Biomarkers of the cell-of-origin/pancreatic cancer stem cell identified by Project 4 will be used to assess specific responses to therapy and roles in relapse/progression. . These studies, in engineered mouse models of de novo pancreatic cancer, will characterize in unprecedented detail the aberrant lesional microenvironment and its regulation by genetic mutations during multistage progression, and begin knowledge-based pre-clinical therapeutic trials with the potential to reveal strategies that could be translated into improved treatments for the human disease.