An advanced in vitro bladder cancer model integrating bladder cancer spheroids into a healthy human urothelium for preclinical therapeutic testing

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BACKGROUND: Despite therapy advances, better solutions for refractory bladder cancer remain an unmet need. Human cell-based models may aid in better treatment translation. We introduce 3D-UHU-TU, a bladder cancer microtissue model which incorporates spheroids derived from low- and high-grade human bladder cancer cell lines (RT112 and T24 respectively) into a healthy human urothelium. METHODS: After model characterisation with histopathology and immunofluorescence microscopy, we trialled both the conventional chemotherapeutic Mitomycin C (MMC), and a novel herpes simplex oncolytic virus (oHSV-GFP), each assessed using confocal microscopy and cytotoxicity assays. RESULTS: We observed correct expression of E- and N-Cadherin, CK7, CK20, GATA3 and Ki-67, alongside invasion and migration phenotypes. MMC treatment caused cell lysis and nuclear damage in cancer spheroids in both low- and high-grade models, with minimal damage to the surrounding healthy urothelium, and a significant increase in cleaved caspase 3 in low-grade models. oHSV-GFP co-localised in cancer spheroids and induced syncytia, spheroid disaggregation and cytotoxicity with minimal to no co-localisation or cytotoxicity in the healthy urothelium. CONCLUSION: 3D-UHU-TU model is useful for testing both treatment safety and efficacy on different grades of bladder cancer. Future use of primary tumour spheroids in place of cell lines may allow a personalised medicine approach.

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