Mouse Model of Pancreatic Tumorigenesis with Dysregulation of mTOR

mTOR 失调的小鼠胰腺肿瘤发生模型

• 批准号: 7535942
• 负责人: MARSHA L. FRAZIER
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-06 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535942
• 关键词: Age; Age-Months; Appearance; Breast; Cancer Etiology; Colon; Data; Development; Disease; Ductal; Embryo; Epithelial; Exons; Future; Gene Targeting; General Population; Genes; Genotype; Genus Cola; Germ-Line Mutation; Goals; Hamartoma; Hamartomatous Polyp; Human; Hyperpigmentation; Knock-out; Knockout Mice; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of pancreas; Metaplasia; Modeling; Mucinous Neoplasm; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Ovary; Pancreas; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Peutz-Jeghers Syndrome; Prevention; Process; Public Health; Publishing; Purpose; Relative Risks; Reporting; Risk; Role; STK11 gene; Signal Pathway; Signal Transduction; Sirolimus; Small Intestines; Stomach; Structure; Study models; TP53 gene; Therapeutic Agents; Time; Tissues; Transgenes; Tuberous sclerosis protein complex; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Up-Regulation; Woman; analog; base; cancer therapy; carcinogenesis; embryonic stem cell; gastrointestinal; knockout gene; malformation; men; mortality; mouse model; pancreatic neoplasm; pancreatic tumorigenesis; polyposis; tumorigenesis

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth most common cause of cancer mortality in men and women in the United States. It is one of the most lethal cancers, with most patients dying within a year. LOH at the LKB1 locus is seen in approximately 32% of pancreatic tumors suggesting its involvement in pancreatic tumorigenesis. The tumor suppressor LKB1 has been shown to be a negative regulator of mTOR [mammalian target of rapamycin] signaling via AMPK activation of the tuberous sclerosis complex 2 (TSC2). The mTOR signaling pathway has been reported to be constitutively activated in a high proportion of pancreatic cancers. Germline mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), a disorder characterized by mucocutaneous hyperpigmentation and gastrointestinal hamartomatous polyps which display dysregulation of mTOR signaling. In addition, patients with PJS also have a dramatically increased risk for development of a variety of epithelial neoplasias. The relative risk for pancreatic cancer has been estimated to be 132 times that of the general population. The overall goal of this proposal is to develop a mouse model for pancreatic adenocarcinoma with dysregulation of mTOR via deficiency in LKB1. This will be accomplished by generating a mouse line that is homozygous for the conditional knockout genes of LKB1 and p53. Based on our previous studies demonstrating that mutations in LKB1 and p53 can cooperate to accelerate the tumorigenesis of gastrointestinal hamartomas, we hypothesize that mutations in LKB1 and p53 will cooperate to accelerate tumorigenesis and that these mice will develop pancreatic cancer. Preliminary observations in mice carrying the LKB1 conditional knockout, the PDXCre transgene, and wild type p53 indicate that pancreatic acinar-to-ductal metaplasia develops at 2-3 months of age. Metaplasia is a harbinger of cancer in many tissues. As the mice age, they develop cystic malformations that resemble the intrapapillary mucinous neoplasms (IPMNs) seen in humans with PJS as well as sporadic cases. IPMNs are considered precursors of pancreatic cancer, however these mice do not survive long enough to develop pancreatic cancer due to the expansion of the IPMN-like structures. It is hypothesized that pancreas specific deletion of p53, in addition to LKB1, will accelerate the process of tumorigenesis and the IPMN-like structures will progress to pancreatic adenocarcinoma. Once mice with pancreas specific deletion of p53 and LKB1 have been generated, the timing of appearance and the development of any histological changes in the pancreata of these mice will be assessed. Because inactivation of LKB1 has been shown to result in inactivation of AMPK, leading to dysregulation of mTOR signaling, we hypothesize that we will observe dysregulation of mTOR in the context of the pancreatic cancer in these mice. mTOR is a target for cancer therapy and prevention. If these mice develop pancreatic adenocarcinoma, they will serve as a valuable new model for conducting future studies on targeted therapy directed toward the mTOR pathway. If mutations in LKB1 and p53 cooperate in the process of tumorigenesis, these mice will serve as an exciting new model for studying the mechanisms by which LKB1 and p53 mutations interact in pancreatic adenocarcinoma. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth most common cause of cancer mortality in men and women in the United States. Close to 100% of the patients with pancreatic cancer develop metastasis. Dysregulation of the mTOR pathway is common in pancreatic adenocarcinoma. This mouse model will be useful in studying the dysregulation of the mTOR pathway and its potential as a target for prevention and treatment of this disease. A secondary goal will be to determine if mutations in LKB1 and p53 cooperate in pancreatic tumorigenesis. Mutations in LKB1 and p53 were previously found to cooperate in a study on a mouse model of polyposis. 1

描述（由申请人提供）：胰腺癌是美国男性和女性癌症死亡率的第四大原因。它是最致命的癌症之一，大多数患者在一年内死亡。在大约32％的胰腺肿瘤中可以看到LKB1基因座处的LOH，这表明其参与胰腺肿瘤发生。肿瘤抑制剂LKB1已被证明是通过AMPK激活结节性硬化症复合物2（TSC2）的AMPK激活，是MTOR的负调节剂[Rapamycin的哺乳动物靶标]。据报道，MTOR信号通路以高比例的胰腺癌组成性激活。 LKB1中的生殖线突变引起Peutz-Jeghers综合征（PJS），这种疾病为特征，其特征是粘膜皮肤色素沉着和胃肠道hamartomatos息肉，这些息肉表现出MTOR信号传导失调的失调。此外，PJS患者的发展风险也大大增加了各种上皮肿瘤的风险。胰腺癌的相对风险估计是普通人群的132倍。该提案的总体目标是开发胰腺腺癌的小鼠模型，并通过LKB1缺乏对MTOR的失调。这将通过生成一条对LKB1和p53的有条件敲除基因纯合的小鼠系来实现。基于我们先前的研究表明，LKB1和p53中的突变可以合作加速胃肠道腺瘤的肿瘤发生，我们假设LKB1和p53中的突变将合作以加速肿瘤发生，并且这些小鼠将患上胰腺癌。携带LKB1有条件敲除的小鼠，PDXCRE转基因和野生型p53的初步观察表明，胰腺腺泡到导向性过失时期在2-3个月大时才出现。 Metaplasia是许多组织中癌症的预兆。随着小鼠的年龄，它们会发展出类似于患有PJS和零星病例的人类中毛细血管内粘液性肿瘤（IPMN）的囊性畸形。 IPMN被认为是胰腺癌的前体，但是由于IPMN样结构的扩展，这些小鼠的生存时间不能足够长，无法患上胰腺癌。假设p53的胰腺特异性缺失除LKB1外还将加速肿瘤发生过程，而IPMN样结构将发展为胰腺腺癌。一旦产生了p53和lkb1的特异性缺失的小鼠，将评估外观的时机和这些小鼠胰腺的任何组织学变化的时间。由于已证明LKB1的失活导致AMPK失活，导致MTOR信号传导失调，因此我们假设我们将观察到这些小鼠胰腺癌中MTOR的失调。 MTOR是癌症治疗和预防的目标。如果这些小鼠发生胰腺腺癌，它们将成为对针对MTOR途径的靶向治疗进行未来研究的宝贵新模型。如果LKB1和p53中的突变在肿瘤发生过程中配合，则这些小鼠将作为研究LKB1和p53突变在胰腺腺癌中相互作用的机制的令人兴奋的新模型。公共卫生相关性：胰腺癌是美国男性和女性癌症死亡率的第四大原因。胰腺癌患者中，近100％会发生转移。 MTOR途径的失调在胰腺腺癌中很常见。该小鼠模型将有助于研究MTOR途径的失调及其作为预防和治疗该疾病的潜力。次要目标是确定LKB1和p53中的突变是否在胰腺肿瘤发生中合作。先前在一项关于小鼠多息护物模型的研究中发现了LKB1和p53中的突变。 1