Pancreafic adenocarcinomas are characterized by extensive deposition of collagen 1, which can have profound effects on cell behavior. We have shown that cells derived from pancreatic adenocarcinomas respond In vitro to exogenous collagen I by transforming from a non-motile epithelial cell to a highly motile and invasive mesenchymal cell. A hallmark of epithelial to mesenchymal transition is an increase in expression of the mesenchymal cadherin, N-cadherin. Keith's lab has been studying the role of N-cadherin in tumor progression for more than a decade, and we have convincingly demonstrated that upregulafion of N-cadherin expression converts epithelial cells from benign, non-mofile, non-invasive cells to highly mofile and invasive cells. From these studies, we hypothesized that N-cadherin promotes tumor cell invasion. Clinical studies from our lab and others have validated our hypothesis. Of particular significance to the current proposal is the fact that Ncadherin is expressed by more than 50% of invasive pancreatic tumors. Here, long-temn goal is to determine the molecular basis of N-cadherin-mediated invasiveness and metastasis in PC. Previous studies from our lab have demonstrated that N-cadherin knockdown in BxPC3 and Capani pancreatic adenocarcinoma cells can significantly decrease tumor progression and metastasis in orthotopic xenograft models. However, the role of individual components of the tumor microenvironment is not cleariy understood. Genetically engineered mouse models have been shown to faithfully mimic the genefic and biological evolufion of their human counterpart diseases. The hypothesis is that N-cadherin expression In multiple components of tumor microenvironment is critical for PC metastasis. We propose to test the hypothesis by generafing and ufilizing syngeneic tumor implantafion models with alterafions in N-cadherin expression in individual components of PC microenvironment. In addition to the critical role of N-cadherin expression in pancreafic adenocarcinoma cells in promoting cancer and metastasis, N-cadherin is also expressed and involved in the mofility of stellate cells as well as macrophages. Both, pancreafic stellate cells and macrophages have been shown to facilitate tumorigenesis and invasiveness of pancreatic adenocarcinoma cells. Thus, we further hypothesize that N-cadherin expression on pancreatic stellate cells and macrophages facilitates PC progression and invasion. Hence, we propose to test the relative contribufion of N-cadherin expression on stellate cells and macrophages toward PC progression and invasion by proposing the following specific aims:
Aim 1 : To determine the contribufion of N-cadherin-mediated adenocarcinoma cell-stromal cell interacfions in PC. Our working hypothesis of this aim is that N-cadherin mediates tumor-stromal interactions and N-cadherin expression on stromal cells facilitates their tumor recruitment.
Aim 2 : To determine the contribufion of N-cadherin-mediated adenocarcinoma cell-macrophage interacfions toward PC invasiveness. Our working hypothesis of this aim is that N-cadherin expression on macrophages facilitates their recruitment and acfivafion in the tumor cell compartments and facilitates PC progression.

Agency
National Institute of Health (NIH)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163120-04
Application #
8711372
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Macha, M A; Rachagani, S; Pai, P et al. (2015) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene 34:1698-708
Wakaskar, Rajesh R; Bathena, Sai Praneeth R; Tallapaka, Shailendra B et al. (2015) Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after I Pharm Res 32:1028-44
Zhu, Yu; Li, Jing; Kanvinde, Shrey et al. (2015) Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer. Mol Pharm 12:332-41
Vaz, A P; Ponnusamy, M P; Rachagani, S et al. (2014) Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells. Br J Cancer 111:486-96
Joshi, Suhasini; Kumar, Sushil; Choudhury, Amit et al. (2014) Altered Mucins (MUC) trafficking in benign and malignant conditions. Oncotarget 5:7272-84
Souchek, J J; Baine, M J; Lin, C et al. (2014) Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. Br J Cancer 111:1139-49
Kaur, Sukhwinder; Sharma, Neil; Krishn, Shiv Ram et al. (2014) MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-*B signaling in pancreatic cancer. Clin Cancer Res 20:688-700
Liu, Xiang; Yi, Chunhui; Wen, Yunfei et al. (2014) Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis. Cancer Res 74:1609-20
Momi, Navneet; Kaur, Sukhwinder; Rachagani, Satyanarayana et al. (2014) Smoking and microRNA dysregulation: a cancerous combination. Trends Mol Med 20:36-47
Stark, Jaime L; Mehla, Kamiya; Chaika, Nina et al. (2014) Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer. Biochemistry 53:1360-72

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