Dec 25, 2019

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

Proceedings of the National Academy of Sciences of the United States of America
Liang WangJung Wook Park

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 de...Continue Reading

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Mentioned in this Paper

Genetically Engineered Mouse
Neoplastic Cell
Neoplasms
Urinary Bladder
Pharmacologic Substance
Carcinoma, Small Cell
RNA, Messenger
Regulation of Protein Expression
Basal Cell of Urothelium
Bladder Small Cell Neuroendocrine Carcinoma

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