Bladder cancer is a common and deadly disease, but the molecular events leading to its development are incompletely understood. We have recently identified a novel oncogene, Ataxia-Telangiectasia Group D Complementing (ATDC), which drives initiation and progression of bladder tumors in transgenic mice. These tumors are indistinguishable from their human counterparts. ATDC expression is elevated (about 70%) in human invasive bladder cancers and correlates with poorer survival after chemotherapy. In other tumor types, ATDC binds p53, modulates DNA damage responses and up-regulates beta-catenin signaling. In preliminary data, we find that ATDC expression is induced by inflammation, associated with decreased expression of PTEN and RB1, two important tumor suppressor genes implicated in bladder tumorigenesis, and show that ATDC promotes methylation and silencing of the PTEN promoter through upregulation of DNMT3a. We hypothesize that ATDC is a crucial determinant of formation, progression and the cytotoxic response in bladder cancer. To better understand the role of ATDC in bladder cancer, we propose the following studies:
AIM 1 : To characterize the role of ATDC in bladder cancer initiation, progression and metastasis using novel transgenic mouse models and determine the role of inflammation in inducing ATDC expression in normal urothelium.
AIM 2 : To characterize the role of PTEN, RB1 and p53 in ATDC-mediated bladder tumor formation and progression using both human and mouse model systems.
AIM 3 : To determine if ATDC expression in bladder cancer drives progression to invasive disease.
AIM 4 : To determine if ATDC expression promotes bladder tumor resistance to chemotherapy. These studies will characterize a novel mechanism of bladder tumor development and a valuable transgenic model of bladder cancer. We will also use existing human cell lines and primary human tumor samples to elucidate the molecular mechanisms by which ATDC induces bladder cancer and mediates resistance to chemotherapy. These studies are significant because understanding ATDC's oncogenic activity in bladder cancer may lead to new prognostic biomarkers and improved therapeutic approaches in humans.

Public Health Relevance

We propose that ATDC is a marker of aggressive bladder tumors which determines progression and response to chemotherapy. ATDC also represents a novel therapeutic target which may sensitize bladder tumors to chemotherapy and radiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA174836-01A1
Application #
8629316
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2014-04-10
Project End
2019-02-28
Budget Start
2014-04-10
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$445,705
Indirect Cost
$159,078
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
Li, Ling; Hao, Xinbao; Qin, Jun et al. (2014) Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice. Gastroenterology 146:1108-18