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Abstract
To study the progression of bladder cancer from non-muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease. SIGNIFICANCE: Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.

Affiliations

Soonbum Park #  1 , Lijie Rong #  1 , Tomasz B Owczarek #  2 , Matteo Di Bernardo #  1 , Rivka L Shoulson  3 , Chee-Wai Chua  2   4   5   6 , Jaime Y Kim  1 , Amir Lankarani  1 , Prithi Chakrapani  1 , Talal Syed  2   4   5   6   7 , James M McKiernan  2   8 , David B Solit  9   10 , Michael M Shen  2   4   5   6   8 , Hikmat A Al-Ahmadie  11 , Cory Abate-Shen  12   2   6   8
1 Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York.
2 Department of Urology, Columbia University Irving Medical Center, New York, New York.
3 Institute of Comparative Medicine, Columbia University, New York, New York.
4 Department of Medicine, Columbia University Irving Medical Center, New York, New York.
5 Department of Genetics & Development, Columbia University Irving Medical Center, New York, New York.
6 Department of Systems Biology, Columbia University Irving Medical Center, New York, New York.
7 Department of Biological Sciences, Columbia University, New York, New York.
8 Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
9 Departments of Human Oncology and Pathogenesis and Medicine, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
10 Weill Medical College, Cornell University, New York, New York.
11 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
12 Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York. cabateshen@columbia.edu.
# Contributed equally.