Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 1, Pages 563-572Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1915770117
Keywords
cancer phenotypes; cell surface protein; urothelial cell; preclinical model
Categories
Funding
- UCLA Broad Stem Cell Research Center postdoctoral fellowship
- Prostate Cancer Foundation
- NIH/NCI Grant K99/R00 Pathway to Independence Award [K99CA218731]
- Gaba Broad Stem Cell Research Center Innovation Award
- Perkins Foundation
- NIH/NCI R01 Grant [CA222877]
- UCLA Specialized Program of Research Excellence (SPORE) in Prostate Cancer [NIH P50 CA092131]
- Medical Research Grant Program of the W. M. Keck Foundation
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Hal Gaba Fund for Prostate Cancer Research
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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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