Pd14-01 Orthotopic Murine Model of Neuroendocrine Bladder Cancer Elucidates Potential Molecular Drivers of Small Cell Bladder Cancer (Scbc)

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (PD14)1 May 2024PD14-01 ORTHOTOPIC MURINE MODEL OF NEUROENDOCRINE BLADDER CANCER ELUCIDATES POTENTIAL MOLECULAR DRIVERS OF SMALL CELL BLADDER CANCER (SCBC) Ross Liao, Jarrell Imamura, Hui Ting Ruan Li, Andrew Muskara, Shinjini Ganguly, Chris McFarland, Aysegul Balyimez, Moshe Ornstein, Shilpa Gupta, Jesse McKenney, Eric Klein, Christopher Weight, Nima Almassi, and Omar Mian Ross LiaoRoss Liao , Jarrell ImamuraJarrell Imamura , Hui Ting Ruan LiHui Ting Ruan Li , Andrew MuskaraAndrew Muskara , Shinjini GangulyShinjini Ganguly , Chris McFarlandChris McFarland , Aysegul BalyimezAysegul Balyimez , Moshe OrnsteinMoshe Ornstein , Shilpa GuptaShilpa Gupta , Jesse McKenneyJesse McKenney , Eric KleinEric Klein , Christopher WeightChristopher Weight , Nima AlmassiNima Almassi , and Omar MianOmar Mian View All Author Informationhttps://doi.org/10.1097/01.JU.0001009472.76470.8c.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: SCBC is a rare, aggressive bladder cancer. Defining mutations of neuroendocrine (NE) cancers include mutations in p53/Rb and MYC. We engineered an orthotopic mouse model of SCBC by targeted induction of driver mutations to investigate the development of SCBC. METHODS: Lentiviral (LV) particles carrying Cre recombinase (CR) were generated from cell culture. Bladders of genetically engineered Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) mice were transduced with CR-expressing LV via transurethral cath (TC). Micro-ultrasound (mUS) and bioluminescent imaging (BI) were used to monitor tumors which were histologically verified on H&E and immunohistochemistry (IHC). Whole transcriptome (RNAseq) analysis was used to correlate transcriptomic profile of NE mouse to human SCBC tumors. Candidate genes and their prognostic association in human SCBC were evaluated (TCGA BLCA, n=417). Forkhead box proteins were investigated in 39 human SCBCs and murine syngeneic cell lines. RESULTS: Upon TC, RPM mice developed SCBC visible on mUS and BI within 8-12 weeks. Mice with intravesical tumors developed spontaneous metastases (Figure 1). NE morphology and markers were confirmed on H&E and IHC by a GU pathologist. Western blot confirmed increased Myc and suppression of TP53/RB1. Transcriptomic profiling of mouse and human SCBC demonstrated concordant gene expression (Figure 2). Gene expression profiling of mouse NE bladder tumors and normal bladder showed increased intratumoral FOXA2 expression, confirmed on IHC. TCGA-BLCA analysis showed worse overall survival for patients whose tumors overexpressed FOXA2 (p=0.01). Expression of FOXA2 in human urothelial cancer lines harboring p53 and RB mutations led to increased NE marker expression by IHC. CONCLUSIONS: We developed a novel genetically engineered orthotopic murine model of SCBC histologically and morphologically similar to human SCBC. Gene expression analysis of NE mouse and human bladder tumors showed upregulation of FOXA2 and suggest its importance in SCBC development. Download PPTDownload PPT Source of Funding: Grant funding from Department of Defense and American Cancer Society © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e353 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Ross Liao More articles by this author Jarrell Imamura More articles by this author Hui Ting Ruan Li More articles by this author Andrew Muskara More articles by this author Shinjini Ganguly More articles by this author Chris McFarland More articles by this author Aysegul Balyimez More articles by this author Moshe Ornstein More articles by this author Shilpa Gupta More articles by this author Jesse McKenney More articles by this author Eric Klein More articles by this author Christopher Weight More articles by this author Nima Almassi More articles by this author Omar Mian More articles by this author Expand All Advertisement PDF downloadLoading ...