A Genetically Defined Disease Model Reveals that Urothelial Cells Can Initiate Divergent Bladder Cancer Phenotypes - Beyond the Abstract

Our recently published manuscript described an epithelial transformation system that generated a novel small cell carcinoma of the bladder (SCCB) model. A surprising finding was that a genetically defined single-cell clone could represent multiple phenotypes in our xenograft model. This implicates epigenetic regulation as masters of phenotypic and subtype diversity. Current strategies will investigate these factors as well as evaluate the roles of other common genetic alternations in bladder cancer, such as H-Ras and FGFR3 mutations in cancer initiation.
Our work also suggested that SCCB patients may benefit from anti-PD-1/PD-L1 therapies with similar levels of PD-L1 expression compared to muscle-invasive bladder cancer patients in both tumor cells and tumor-infiltrating lymphocytes. Previous work using this epithelial transformation system showed the development of small cell neuroendocrine tumors from prostate and lung epithelium, suggesting commonalities in their biology. In parallel with developing our manuscript, we proposed and initiated the ongoing clinical trial treating SCCB and naïve and treatment-induced neuroendocrine prostate cancer patients with pembrolizumab combined with chemotherapy. This strategy has since been validated with trials in small cell lung cancer (SCLC) patients and FDA approval of combinational use of checkpoint inhibitors and chemotherapy in this population.

Written by: Liang Wang, Bryan A Smith, Nikolas G Balanis, Brandon L Tsai, Kim Nguyen, Michael W Cheng, Matthew B Obusan, Favour N Esedebe, Saahil J Patel, Hanwei Zhang, Peter M Clark, Anthony E Sisk, Jonathan W Said, Jiaoti Huang, Thomas G Graeber, Owen N Witte, Arnold I Chin, Jung Wook Park

Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA., Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA., Department of Urology, University of California, Los Angeles, CA., Department of Pathology, University of California, Los Angeles, CA., Department of Pathology, School of Medicine, Duke University, Durham, NC., Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA; Department of Urology, University of California, Los Angeles, CA.

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