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.
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
| Liu, Qian; Chen, Jinyun; Wang, Jin et al. (2014) Putative tumor suppressor gene SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma. Mol Carcinog 53:711-21 |
| Huang, Yu-Jing; Frazier, Marsha L; Zhang, Nianxiang et al. (2014) Reverse-phase protein array analysis to identify biomarker proteins in human pancreatic cancer. Dig Dis Sci 59:968-75 |
