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(申请人提供)：胰腺癌是美国男性和女性癌症死亡的第四大常见原因。它是最致命的癌症之一，大多数患者在一年内死亡。LKB1基因的杂合性缺失见于大约32%的胰腺肿瘤中，提示其与胰腺肿瘤的发生有关。肿瘤抑制基因LKB1通过激活结节性硬化症复合体2(TSC2)的AMPK，对mTOR[哺乳动物雷帕霉素靶标]信号起负向调节作用。据报道，mTOR信号通路在很高比例的胰腺癌中被结构性激活。LKB1基因的胚系突变导致Peutz-Jeghers综合征(PJS)，PJS是一种以黏膜皮肤色素沉着和胃肠道错构瘤性息肉为特征的疾病，表现为mTOR信号调节失调。此外，PJS患者发生各种上皮性肿瘤的风险也显著增加。胰腺癌的相对风险估计是普通人群的132倍。这项建议的总体目标是建立一种胰腺癌小鼠模型，该模型通过缺乏LKB1而导致mTOR调节失调。这将通过产生条件基因LKB1和P53纯合的小鼠品系来实现。根据我们之前的研究表明，LKB1和P53的突变可以协同促进胃肠道错构瘤的肿瘤发生，我们假设LKB1和P53的突变将协同促进肿瘤的发生，这些小鼠将发展为胰腺癌。对携带LKB1条件基因敲除、PDXCre转基因和野生型p53的小鼠的初步观察表明，胰腺腺泡到导管的化生在2-3个月龄时发生。在许多组织中，化生是癌症的先兆。随着年龄的增长，它们会出现囊性畸形，类似于患有PJS的人类乳头内粘液肿瘤(IPMN)以及散发性病例。IPMN被认为是胰腺癌的前体，然而，由于IPMN样结构的扩张，这些小鼠无法存活足够长的时间而患上胰腺癌。推测除LKB1外，胰腺特异缺失的P53基因将加速肿瘤的发生，IPMN样结构将进展为胰腺癌。一旦产生了胰腺特异性p53和LKB1缺失的小鼠，这些小鼠的胰腺出现的时间和任何组织学变化的发展将被评估。由于LKB1的失活已被证明导致AMPK失活，导致mTOR信号的失调，我们假设我们将在这些小鼠的胰腺癌的背景下观察到mTOR的失调。MTOR是癌症治疗和预防的靶点。如果这些小鼠发生胰腺癌，它们将成为未来针对mTOR途径进行靶向治疗的有价值的新模型。如果LKB1和P53突变在肿瘤发生过程中协同作用，这些小鼠将成为研究LKB1和P53突变在胰腺癌中相互作用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的第四大常见原因。近100%的胰腺癌患者发生转移。MTOR途径的失调在胰腺癌中很常见。这种小鼠模型将有助于研究mTOR通路的失调及其作为预防和治疗这种疾病的靶点的潜力。第二个目标将是确定LKB1和P53的突变是否在胰腺肿瘤发生中协同作用。此前，在一项关于小鼠息肉病模型的研究中，发现LKB1和P53的突变是协同作用的。1