Genetic Approaches to Pancreatic Cancer Progression

胰腺癌进展的遗传学方法

• 批准号: 8517600
• 负责人: KEPING XIE
• 金额: $ 23.91万
• 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/8517600
• 关键词: Ablation; Attenuated; Cancer cell line; Data; Development; Disease; Epigenetic Process; Epithelial Cells; Event; Exhibits; Genetic; Genetic Engineering; 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/总结 转移性胰腺癌是一种致命的疾病。遗传和表观遗传的改变及其后果 胰腺癌发生和进展背后的分子信号变化仍不清楚。我们的 最近的研究表明 FoxM1 蛋白表达在原发性胰腺中急剧增加 与正常胰腺组织中的癌症相比。一致地，人类胰腺癌细胞 FoxM1 表达显着增加。胰腺癌细胞中FoxM1的表达水平 与转移潜能直接相关。 FoxM1 基因工程过度表达促进 人类胰腺癌在异种移植模型中的生长和转移，而 FoxM1 敲除则 对面的。重要的是，小鼠胰腺中 KLF4 的特异性消融会导致 FoxM1 过度表达。 FoxM1 过度表达和 KLF4 表达不足在胰腺肿瘤中很明显 L-KrasG12D/+；pdx1-cre+ 小鼠。我们假设肿瘤抑制因子的遗传和表观遗传变化 癌基因和随后的 FoxM1 信号改变严重影响胰腺癌的发展 和进展。 为了检验我们的假设，我们提出以下三个具体目标： 1. 确定 FoxM1 的因果作用 使用基因工程小鼠模型研究胰腺癌发生和进展中的信号传导。我们 将检验我们的假设，即 FoxM1 的过度表达是激活的 Kras 介导的胰腺中的关键事件 致癌作用；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缺失与Kras癌基因激活的偶然配合 胰腺癌的发生和进展。我们将检验我们的假设，即延迟发生或不存在 KLF4 缺失或激活的 Kras 小鼠模型中的侵袭性癌症可能需要获得额外的遗传信息 和/或表观遗传改变，KLF4 的缺失可能与 Kras 的激活协同作用；从而减少 小鼠中 KLF4 的缺失或缺失会促进 Kras 介导的胰腺癌发生。 3. 确定 KLF4 功能丧失与 FoxM1 表达和功能失调之间的机制关系 胰腺上皮细胞。我们将检验我们的假设，即 KLF4 转录抑制 福克斯M1；胰腺癌发生过程中 KLF4 的缺失导致 FoxM1 过度表达；因此遗传 FoxM1 的缺失将逆转 KLF4 缺失小鼠胰腺的癌前和恶性表型。 这三个具体目标都有我们各自的初步数据支持，可以独立测试 使用我们独特的研究资源，但它们高度相互关联并相互支持。我们预测 这些研究的完成将为分子和遗传基础提供富有洞察力的信息 胰腺癌发病机制和分子靶标的鉴定，以设计有效的预防和治疗 治疗策略。从长远来看，我们的研究还可以导致分子的进一步研究 介导 FoxM1 信号传导失调及其与 ras 和 KLF4 通路串扰的机制。