Genetic Approaches to Pancreatic Cancer Progression

描述（由申请人提供）：转移性胰腺癌是一种致死性疾病。胰腺癌发生和进展背后的遗传和表观遗传改变以及随之而来的分子信号变化仍不清楚。我们最近的研究表明，与正常胰腺组织相比，FoxM 1蛋白在原发性胰腺癌中的表达显著增加。因此，人胰腺癌细胞表现出FoxM 1表达的显著增加。胰腺癌细胞中FoxM 1的表达水平与转移潜能直接相关。基因工程过表达FoxM 1促进异种移植模型中人胰腺癌的生长和转移，而FoxM 1敲低则相反。重要的是，小鼠胰腺中KLF 4的特异性消融导致FoxM 1过表达。在L-KrasG 12 D/+; pdx 1-cre+小鼠中发生的胰腺肿瘤中，FoxM 1的过度表达和KLF 4的低表达是明显的。我们推测，肿瘤抑制基因和癌基因的遗传和表观遗传变化以及随之而来的FoxM 1信号转导的改变严重影响胰腺癌的发生和发展。为了验证我们的假设，我们提出了以下三个具体目标：1。使用基因工程小鼠模型确定FoxM 1信号在胰腺癌发展和进展中的因果作用。我们将检验我们的假设，即FoxM 1的过表达是激活的Kras介导的胰腺癌发生的关键事件，因此基因减少或缺失FoxM 1将减弱K-ras介导的胰腺癌发生。2.探讨KLF 4基因缺失与Kras癌基因激活在胰腺癌发生发展中的协同作用。我们将检验我们的假设，即在KLF 4缺失或激活的Kras小鼠模型中，浸润性癌症的延迟发作或不存在可能需要获得额外的遗传和/或表观遗传改变，并且KLF 4的缺失可能与Kras的激活合作;因此，小鼠中KLF 4的减少或缺失应促进Kras介导的胰腺癌发生。3.确定胰腺上皮细胞中KLF 4功能丧失与FoxM 1表达和功能失调之间的机制关系。我们将验证我们的假设，即KLF 4转录抑制FoxM 1的表达;胰腺癌发生过程中KLF 4的缺失导致FoxM 1的过度表达;因此，FoxM 1的基因缺失将逆转KLF 4缺失小鼠胰腺癌前和恶性表型。这三个具体目标得到了我们各自的初步数据的支持，并且可以使用我们独特的研究资源进行独立测试，但它们高度相关并相互支持。我们预测，这些研究的完成将为胰腺癌发病机制的分子和遗传基础提供有见地的信息，并确定分子靶点，以设计有效的预防和治疗策略。从长远来看，我们的研究也可以导致进一步研究介导FoxM 1信号失调及其与ras和KLF 4通路的串扰的分子机制。 公共卫生相关性：FoxM 1的过表达与肿瘤发生有关，而FoxM 1信号转导失调及其对胰腺癌进展的影响的因果机制知之甚少。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Overexpression of FoxM1 is associated with tumorigenesis, while little is known for the causal mechanisms underlying dysregulated FoxM1 signaling and its impact on pancreatic cancer progression.