Novel mouse models of bladder cancer identify a prognostic signature associated with risk of disease progression Journal Article
| Authors: | Park, S.; Rong, L.; Owczarek, T. B.; Di Bernardo, M.; Shoulson, R. L.; Chua, C. W.; Kim, J. Y.; Lankarani, A.; Chakrapani, P.; Syed, T.; McKiernan, J. M.; Solit, D. B.; Shen, M. M.; Al-Ahmadie, H. A.; Abate-Shen, C. |
| Article Title: | Novel mouse models of bladder cancer identify a prognostic signature associated with risk of disease progression |
| Abstract: | To study 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 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 p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle invasive bladder tumors. Furthermore, pre-invasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including pro-inflammatory 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. © 2021 American Association for Cancer Research Inc.. All rights reserved. |
| Keywords: | adult; controlled study; gene deletion; cancer growth; nonhuman; animal cell; mouse; animal tissue; animal experiment; animal model; inflammation; bladder cancer; protein p53; risk factor; urothelium; basal cell; genetic recombination; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; transgene; tamoxifen; upregulation; adenovirus vector; cre recombinase; bladder carcinogenesis; p53 gene; pten gene; muscle invasive bladder cancer; human versus animal comparison; cancer prognosis; human; male; female; article; genetically engineered mouse strain |
| Journal Title: | Cancer Research |
| Volume: | 81 |
| Issue: | 20 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-10-15 |
| Start Page: | 5161 |
| End Page: | 5175 |
| Language: | English |
| DOI: | 10.1158/0008-5472.Can-21-1254 |
| PROVIDER: | scopus |
| PUBMED: | 34470779 |
| PMCID: | PMC8609963 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2021 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
-
778Solit -
655Al-Ahmadie
Related MSK Work