Mechanisms & Therapeutic Targeting of the Microenvironment in Pancreatic Cancer

项目3将使用之前开发的多阶段胰腺癌形成的小鼠模型和 项目1同时分析研究肿瘤微环境及其组成细胞 类型作为INK4a/Arf、P53和/或Smad4肿瘤抑制基因缺失的功能，以及 PI3Kinase通路，ALL在突变激活的KRAS信号背景下。微环境 要评估的参数包括：血管生成和血管系统的特征； 周细胞与肿瘤血管的关系：淋巴管生成和淋巴管的形态 血管系统；浸润性(肿瘤增强)白细胞的丰度和类型及其表达/活性 它们产生的基质降解酶；以及成纤维细胞基质细胞的特征。 一个中心目标是检验这一假设，即肿瘤的血管生成表型和其他特征 Panin和PDAC的微环境受特定抑癌基因缺失的不同调控 这些基因是这种疾病的标志。与项目2合作实现的一个辅助目标是 目的：确定KRAS信号通过PIS激酶网络在癌细胞中诱导 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将评估在小鼠身上识别的遗传和表型参数之间的相关性。 将建立肿瘤阶段特定的临床前试验设计，并用于测试创新 化疗方案，靶向抗血管生成治疗，以及可能指导未来的组合 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的探测器 微环境参数，用于监测皮损进展和对治疗的反应。 项目4确定的来源细胞/胰腺癌干细胞的生物标记物将用于评估 对治疗的特定反应和在复发/进展中的作用。。 这些研究，在新生胰腺癌的工程化小鼠模型中，将在 异常皮损微环境及其基因突变调控的空前细节 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 这些战略可以转化为改善人类疾病的治疗方法。

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.