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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148954-03
Application #
8304315
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Jhappan, Chamelli
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$254,412
Indirect Cost
$93,392
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Sun, Hongcheng; Tang, Huamei; Xie, Dacheng et al. (2016) Krüppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6. Clin Cancer Res 22:502-12
Wei, Daoyan; Wang, Liang; Yan, Yongmin et al. (2016) KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis. Cancer Cell 29:324-38
Guo, Kun; Cui, Jiujie; Quan, Ming et al. (2016) A novel KLF4-MSI2 signaling pathway regulates growth and metastasis of pancreatic cancer. Clin Cancer Res :
Guo, Junli; Xie, Keping; Zheng, Shaojiang (2016) Molecular Biomarkers of Pancreatic Intraepithelial Neoplasia and Their Implications in Early Diagnosis and Therapeutic Intervention of Pancreatic Cancer. Int J Biol Sci 12:292-301
Cui, J; Xia, T; Xie, D et al. (2016) HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes. Oncogene 35:4708-18
Yan, Yongmin; Li, Zhiwei; Kong, Xiangyu et al. (2016) KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis. Cancer Res 76:2419-31
Quan, Ming; Cui, Jiujie; Xia, Tian et al. (2015) Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling. Cancer Res 75:4778-89
Li, Zhiwei; Guo, Junli; Xie, Keping et al. (2015) Vitamin D receptor signaling and pancreatic cancer cell EMT. Curr Pharm Des 21:1262-7
Xie, Dacheng; Xie, Keping (2015) Pancreatic cancer stromal biology and therapy. Genes Dis 2:133-143
Li, Zhiwei; Jia, Zhiliang; Gao, Yong et al. (2015) Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness. Clin Cancer Res 21:844-53

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