Patient derived models of bladder cancer amplify tumor specific gene expression compared to surgical specimen while maintaining gene expression of molecular subtype and epithelial mesenchymal transition markers

Abstract

Patient derived models (PDMs) are a powerful tool to study preclinical responses. However, the benefits of each model have not been compared head-to-head when models are derived from the same surgical specimen. PDMs derived from surgical specimens were established as xenografts (PDX), organoids (PDO), and spheroids (PDS). PDMs were molecularly characterized by RNA sequencing. Differential gene expression was determined between the PDMs and surgical specimens. Surgical specimens had the most differentially expressed genes reflecting loss of immune and stromal compartments in PDMs. PDMs and surgical specimens were clustered using the Euclidian distance analysis to test model fidelity. PDMs upregulated a clear, patient-specific bladder cancer signal. Overall, the molecular profiles of PDXs were the most similar to the matching patient surgical specimen than the PDO and PDS from that patient. The epithelial mesenchymal transition (EMT) gene expression profile is maintained in the PDMs showing the persistence of EMT in both in vivo and in vitro model setting. The consensus molecular subtype was determined in order to compare PDMs to each other and their matching surgical specimen, and only surgical specimens with Basal/Squamous or Luminal Papillary molecular subtype established PDMs. Patient derived models reduce tumor heterogeneity and allow analysis of specific tumor compartments while maintaining the gene expression profile representative of the original tumor.