Invasive pancreatic cancer (PDA) is a lethal disease. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategie to control PDA progression. Our previous studies have demonstrated that transcription factor FOXM1 is drastically increased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially elevated FOXM1 expression. In sharp contrast, our recent study has shown a consistent lack of vitamin D receptor (VDR) expression in invasive PDA as compared to that in PanINs. Causally linking VDR loss to FOXM1 overexpression and functionally interrogating the underlying mechanisms are fundamentally important in understanding PDA progression. We postulate that downregulation of VDR expression causes FOXM1 overexpression and consequential acquisition of malignant phenotype in PDA, i.e., a switch from PanINs to invasive PDA. Therefore, activation and/or restoration of VDR signaling could attenuate PanINs progression and sensitize PDA to Vitamin D treatment. To test our hypothesis, we propose three specific aims: (1) Determine whether loss of VDR expression is a critical event of pancreatic cancer progression from PanIN to invasive PDA; (2) Determine the critical molecular mechanisms underlying dysregulation of VDR signaling in and its mechanistic impact on PDA progression; and (3) Determine whether an intact VDR signaling renders PanINs sensitive to Vitamin D treatment, while invasive PDA are refractory to Vitamin D due to loss of VDR expression. These three novel specific aims with clinical relevant question (aim 1), mechanistic substantiation (aim 2) and translational validation (aim 3), 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. Our proposed studies will take advantage of the unique resources available at MD Anderson Cancer Center, including our large collection of pancreatic cancer specimens and mouse models. Given the important role of VDR/FOXM1 we have uncovered, we predict that completion of these studies will provide insightful information for the molecular basis of pancreatic cancer progression and for identification of molecular targets to design effective prevention and treatment strategies; and translation of our findings into benefiting PDA patients is our long term goal.

Public Health Relevance

This proposal is designed to determine the epigenetic changes that drive the progression of PanINs to invasive PDA. Our proposed studies will focus on causally linking Vitamin D receptor (VDR) downregulation to FOXM1 overexpression and interrogating the impact of dysregulation of this pathway on PDA progression and its effective intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
United States
Zip Code
Wang, Liang; Zuo, Xiangsheng; Xie, Keping et al. (2018) The Role of CD44 and Cancer Stem Cells. Methods Mol Biol 1692:31-42
Kong, Fanyang; Sun, Tao; Kong, Xiangyu et al. (2018) Krüppel-like Factor 4 Suppresses Serine/Threonine Kinase 33 Activation and Metastasis of Gastric Cancer through Reversing Epithelial-Mesenchymal Transition. Clin Cancer Res 24:2440-2451
Kong, Fanyang; Deng, Xuan; Kong, Xiangyu et al. (2018) ZFPM2-AS1, a novel lncRNA, attenuates the p53 pathway and promotes gastric carcinogenesis by stabilizing MIF. Oncogene 37:5982-5996
Guo, Kun; Cui, Jiujie; Quan, Ming et al. (2017) The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer. Clin Cancer Res 23:687-696
Xie, Victoria K; Li, Zhiwei; Yan, Yongmin et al. (2017) DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression. Clin Cancer Res 23:5585-5597
Zhang, Sicong; Zhao, Boxuan Simen; Zhou, Aidong et al. (2017) m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer Cell 31:591-606.e6
Zhao, Tiansuo; Jiang, Wenna; Wang, Xiuchao et al. (2017) ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin. Cancer Res 77:874-885
Zhou, Aidong; Lin, Kangyu; Zhang, Sicong et al. (2016) Nuclear GSK3? promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nat Cell Biol 18:954-966
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
Xue, Jianfei; Zhou, Aidong; Wu, Yamei et al. (2016) miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis. Cancer Res 76:4293-304

Showing the most recent 10 out of 13 publications