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Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):563-572. doi: 10.1073/pnas.1915770117. Epub 2019 Dec 23.

A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes.

Author information

1
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
2
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
3
Department of Urology, University of California, Los Angeles, CA 90095.
4
Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095.
5
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
6
Department of Pathology, University of California, Los Angeles, CA 90095.
7
Department of Pathology, School of Medicine, Duke University, Durham, NC 27710.
8
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
9
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; owenwitte@mednet.ucla.edu arnoldchin@mednet.ucla.edu jungwook.park@duke.edu.
10
Department of Urology, University of California, Los Angeles, CA 90095; owenwitte@mednet.ucla.edu arnoldchin@mednet.ucla.edu jungwook.park@duke.edu.

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 CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs 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.

KEYWORDS:

cancer phenotypes; cell surface protein; preclinical model; urothelial cell

Conflict of interest statement

Competing interest statement: O.N.W. currently has consulting, equity, and/or board relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, and Allogene Therapeutics. T.G.G. currently has consulting and equity relationships with Trethera Corporation. The laboratory of T.G.G. has completed a research agreement with ImmunoActiva. None of these companies contributed to or directed any of the research reported in this article.

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