Pancreatic adenocarcinoma (PDA) is a deadly disease characterized by late diagnosis, aggressive invasion of surrounding tissues, and early metastasis. Patients with stage 1A disease have a 30% 5 year survival rate following resection, highlighting that PDA metastasizes early in patients, however, the molecular mechanisms driving early metastasis in PDA are not understood. We have recently found that the majority of human pancreatic adenocarcinomas have elevated expression of the Ataxia-Telangiectasia Group D Associated (ATDC) gene and that ATDC has an oncogenic function in pancreatic cancer through Wnt pathway activation and ?-catenin stabilization. Using newly created genetically engineered mouse models of pancreatic cancer, we have now identified a previously unknown role for ATDC in pancreatic cancer, where ATDC is upregulated during the early PanIN stage of tumorigenesis, and in the presence of oncogenic Kras, accelerates PanIN progression and the development of invasive and metastatic tumors. ATDC upregulates CD44 in mouse and human PanIN lesions through a ?-catenin-induced mechanism, resulting in the induction of an epithelial to mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. Knockdown of ATDC blocks invasion in mouse and human PDA cells and this effect is mediated through ?-catenin and CD44. In this proposal, we hypothesize that ATDC is a proximal regulator of EMT and drives progression and metastasis of pancreatic cancer, thus serving as an important therapeutic target. To dissect the role of ATDC in pancreatic cancer, we will: 1) investigate the role of ATDC in pancreatic tumorigenesis using novel genetically engineered mouse models; 2) characterize the molecular mechanisms by which ATDC induces an invasive phenotype in PDA; and 3) determine the mechanism of ATDC upregulation in pancreatic cancer.

Public Health Relevance

ATDC is a new oncogene important in pancreatic cancer progression and metastasis. In this proposal we use novel transgenic mouse models and human samples to examine the role of ATDC in the early stages of pancreatic tumorigenesis to determine the molecular mechanisms by which ATDC promotes an invasive and metastatic phenotype in pancreatic cancer cells. We propose that ATDC is a promising novel therapeutic target in pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA131045-05A1
Application #
8881830
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2007-12-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
$368,422
Indirect Cost
$130,922
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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