Journal article
A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes
Proceedings of the National Academy of Sciences - PNAS, v 117(1), pp 563-572
07 Jan 2020
PMID: 31871155
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSP5 in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSP5 at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.
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Details
- Title
- A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes
- Creators
- Liang Wang - University of California, Los AngelesBryan A. Smith - University of California, Los AngelesNikolas G. Balanis - University of California, Los AngelesBrandon L. Tsai - University of California, Los AngelesKim Nguyen - University of California, Los AngelesMichael W. Cheng - University of California, Los AngelesMatthew B. Obusan - University of California, Los AngelesFavour N. Esedebe - University of California, Los AngelesSaahil J. Patel - University of California, Los AngelesHanwei Zhang - University of California, Los AngelesPeter M. Clark - University of California, Los AngelesAnthony E. Sisk - University of California, Los AngelesJonathan W. Said - University of California, Los AngelesJiaoti Huang - Duke UniversityThomas G. Graeber - University of California, Los AngelesOwen N. Witte - University of California, Los AngelesArnold I. Chin - University of California, Los AngelesJung Wook Park - University of California, Los Angeles
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 117(1), pp 563-572
- Publisher
- Natl Acad Sciences
- Number of pages
- 10
- Grant note
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research CA222877 / NIH/NCI R01 Grant Gaba Broad Stem Cell Research Center Innovation Award UCLA Broad Stem Cell Research Center postdoctoral fellowship Medical Research Grant Program of the W. M. Keck Foundation Hal Gaba Fund for Prostate Cancer Research Prostate Cancer Foundation K99CA218731 / NIH/NCI Grant K99/R00 Pathway to Independence Award; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Perkins Foundation NIH P50 CA092131 / UCLA Specialized Program of Research Excellence (SPORE) in Prostate Cancer
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Web of Science ID
- WOS:000506001200079
- Scopus ID
- 2-s2.0-85077642761
- Other Identifier
- 991019356498304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology