Genetic Approaches to Pancreatic Cancer Progression

胰腺癌进展的遗传学方法

• 批准号: 8304315
• 负责人: KEPING XIE
• 金额: $ 25.44万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304315
• 关键词: Ablation; Attenuated; Cancer cell line; Data; Development; Disease; Engineering; Epigenetic Process; Epithelial Cells; Event; Exhibits; Genetic; Genetically Engineered Mouse; Growth; Human; Investigation; Knockout Mice; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Molecular; Molecular Genetics; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Pancreas; Pathogenesis; Pathway interactions; Premalignant; Preventive; Resources; Role; Signal Transduction; Testing; Therapeutic; Tissues; Tumor Suppressor Genes; Xenograft Model; abstracting; base; carcinogenesis; design; malignant phenotype; mouse model; overexpression; pancreatic cancer cells; pancreatic neoplasm; protein expression; tumor progression; tumorigenesis

Project Abstract/Summary Metastatic pancreatic cancer is a lethal disease. The genetic and epigenetic alterations and consequent changes in molecular signaling behind pancreatic cancer development and progression remain unclear. Our recent studies have shown that FoxM1 protein expression is drastically increased in primary pancreatic cancers when compared with that in normal pancreatic tissue. Consistently, human pancreatic cancer cells exhibit a substantial increase in FoxM1 expression. The levels of FoxM1 expression in pancreatic cancer cells directly correlate with metastatic potential. Genetically engineered overexpression of FoxM1 promotes the growth and metastasis of human pancreatic cancer in xenograft models, while FoxM1 knockdown does the opposite. Importantly, specific ablation of KLF4 in the pancreas of mice results in FoxM1 overexpression. Drastic FoxM1 overexpression and KLF4 underexpression are evident in pancreatic tumors developed in L-KrasG12D/+;pdx1-cre+ mice. We postulate that genetic and epigenetic changes of tumor suppressors and oncogenes and consequent alterations of FoxM1 signaling critically impact pancreatic cancer development and progression. To test our hypothesis, we propose the following three specific aims: 1. Determine the causal role of FoxM1 signaling in pancreatic cancer development and progression using genetically engineered mouse models. We will test our hypothesis that overexpression of FoxM1 is a critical event in activated Kras-mediated pancreatic carcinogenesis; thus genetic reduction or deletion FoxM1 will attenuate K-ras-mediated pancreatic carcinogenesis. 2. Determine the casual cooperation of loss of KLF4 and activation of Kras oncogene in pancreatic cancer development and progression. We will test our hypothesis that delayed onset or absence of invasive cancer in KLF4-null or activated Kras mouse models may require acquisition of additional genetic and/or epigenetic alterations and that a loss of KLF4 may cooperate with an activation of Kras; thus reduction or deletion of KLF4 in mouse should promote Kras-mediated pancreatic carcinogenesis. 3. Determine the mechanistic relationship between loss of KLF4 function and dysregulated FoxM1 expression and function in pancreatic epithelial cells. We will test our hypothesis that KLF4 transcriptionally represses the expression of FoxM1; loss of KLF4 during carcinogenesis of pancreas leads to overexpression of FoxM1; thus genetic deletion of FoxM1 will reverse the premalignant and malignant phenotypes of pancreas in KLF4-null mouse. These three specific aims are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. We predict that completion of these studies will provide insightful information for the molecular and genetic basis of pancreatic cancer pathogenesis and for identification of molecular targets to design effective preventive and therapeutic strategies. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated FoxM1 signaling and its crosstalk with ras and KLF4 pathways.

项目摘要/摘要 转移性胰腺癌是一种致命疾病。遗传和表观遗传改变以及随之而来的 胰腺癌发育和进展背后的分子信号传导的变化尚不清楚。我们的 最近的研究表明，原代胰腺中FOXM1蛋白的表达急剧增加 与正常胰组织中的癌症相比。一贯，人胰腺癌细胞 FOXM1表达的大幅增加。胰腺癌细胞中FOXM1表达的水平 与转移电位直接相关。 FOXM1的基因工程过表达促进了 异种移植模型中人类胰腺癌的生长和转移，而FOXM1敲低做 对面的。重要的是，小鼠胰腺中KLF4的特异性消融导致FOXM1过表达。 在胰腺肿瘤中显而易见的FOXM1过表达和KLF4不渗透是显而易见的 l-krasg12d/+; pdx1-cre+小鼠。我们假设肿瘤抑制子的遗传和表观遗传变化以及 癌基因及其随之而来的FOXM1信号的改变严重影响胰腺癌的发展 和进展。 为了检验我们的假设，我们提出以下三个特定目的：1。确定FOXM1的因果作用 使用基因工程小鼠模型的胰腺癌发育和进展中的信号传导。我们 将测试我们的假设，即FOXM1的过表达是激活的KRAS介导的胰腺的关键事件 癌变；因此，遗传减少或缺失FOXM1将减弱K-RAS介导的胰腺 致癌作用。 2。确定KLF4损失的随意合作和Kras Oncogene的激活 胰腺癌的发展和进展。我们将测试我们的假设，该假设延迟发作或不存在 KLF4-NULL或活化的KRAS小鼠模型中的侵入性癌可能需要获取其他遗传 和/或表观遗传改变，而KLF4的损失可能会与Kras的激活合作；因此还原 或小鼠中KLF4的缺失应促进KRAS介导的胰腺癌发生。 3。确定 KLF4功能丧失与FOXM1表达失调和功能之间的机械关系 胰腺上皮细胞。我们将检验我们的假设，即KLF4转录抑制了 FOXM1;胰腺癌发生期间KLF4的丧失导致FOXM1过表达；因此遗传 FOXM1的删除将逆转KLF4-NULL小鼠中胰腺的前态和恶性表型。 这三个特定目标得到了我们各自的初步数据的支持，可以独立测试 使用我们独特的研究资源，但是它们是高度相互关联的，并互相支持。我们预测 这些研究的完成将为分子和遗传基础提供深刻的信息 胰腺癌的发病机理和用于设计有效预防性和的分子靶标 治疗策略。从长远来看，我们的研究还可以进一步研究分子 介导无调的FOXM1信号传导及其与RAS和KLF4途径的串扰的机制。