Patient-derived organoid mixed hollow-solid phenotypes associate with drug response and worse clinical outcome in muscle-invasive bladder cancer

Abstract Muscle-invasive bladder cancer (MIBC) is marked by histological and molecular heterogeneity, leading to recurrence and therapy resistance. Current management relies on stage, grade, and performance status, yielding broad treatment categories and a “one-size-fits-all” approach that lacks personalization. Patient-derived organoids (PDOs) preserve parental tumor complexity and offer realistic platforms for drug screening and precision medicine. In this study, fresh MIBC specimens were collected from surgical resections. Established PDOs were classified by bright-field morphology (solid, hollow, mixed) and screened against standard chemotherapies and selected FDA-approved agents (tyrosine kinase, mTOR, and PARP inhibitors, as repurposing candidates). Viability was measured using CellTiter-Glo. PDOs exhibited distinct morphologies. Mixed solid-hollow structures correlated with shorter progression-free survival and a broadly resistant drug-response profile across tested compounds, a pattern replicated in an independent cohort. Overall, a simple microscopy-based PDO phenotyping may provide a rapid, accessible functional layer to complement conventional clinicopathological stratification in MIBC. Integrating morphology with organoid drug screening offers a scalable platform for biomarker discovery and hypothesis generation, warranting validation in larger, independent cohorts.