Abstract
Bladder cancer is among the most prevalent cancers worldwide. Currently, few bladder cancer models have undergone thorough characterization to assess their fidelity to patient tumors, especially upon propagation in the laboratory. Here, we establish and molecularly characterize CoCaB 1, an aggressive cisplatin-resistant muscle-invasive bladder cancer patient-derived xenograft (PDX) and companion organoid system. CoCaB 1 was a subcutaneous PDX model reliably transplanted in vivo and demonstrated an acceleration in growth upon serial transplantation, which was reflected in organoid and 2D cell culture systems. Transcriptome analysis revealed progression towards an increasingly proliferative and stem-like expression profile. Gene expression differences between organoid and PDX models reflected expected differences in cellular composition, with organoids enriched in lipid biosynthesis and metabolism genes and deprived of extracellular components observed in PDXs. Both PDX and organoid models maintained the histological fidelity and mutational heterogeneity of their parental tumor. This study establishes the CoCaB 1 PDX and organoid system as companion representative tumor models for the development of novel bladder cancer therapies.
Highlights
Bladder cancer is among the most prevalent cancers worldwide
There has been limited comparison between bladder cancer patient-derived xenograft (PDX) and organoid models to dissect the evolution of their growth dynamics and molecular profiles relative to their parental tumor
A tumor from a muscle-invasive bladder cancer (MIBC) patient refractory to cisplatin-based chemotherapy was used for ex vivo model establishment and growth dynamic studies (Fig. 1A)
Summary
Few bladder cancer models have undergone thorough characterization to assess their fidelity to patient tumors, especially upon propagation in the laboratory. We establish and molecularly characterize CoCaB 1, an aggressive cisplatin-resistant muscle-invasive bladder cancer patient-derived xenograft (PDX) and companion organoid system. This study establishes the CoCaB 1 PDX and organoid system as companion representative tumor models for the development of novel bladder cancer therapies. PDX and organoid systems are promising tools for preclinical testing of novel therapeutics and for precision medicine To validate their utility as clinical models, they require extensive functional and molecular characterization to establish their fidelity to human bladder cancers. In vivo propagation selected for more proliferative and stem-like phenotypes, consistent with observations in breast and hematopoietic cancers[18,19] This aggressive growth advantage was maintained in ex vivo organoid models. Our study highlights the value of PDXs and organoids as representative tumor models for the development of novel bladder cancer therapies
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