Molecular subtypes of bladder cancer do not display microenvironment- or metastasis-induced plasticity

Background Transcriptomic and genomic analyses of bladder cancer (BC) reveal a highly diverse disease stratified into molecular subtypes with distinct molecular features and biological behaviors. Intratumor heterogeneity (ITH) and plasticity can significantly impact diagnosis and patient management, yet their extent in BC remains highly debated. Methods Here, we investigated whether the three main bladder cancer subtypes maintain or alter their identity in response to changes in the microenvironment and during metastatic colonization. Results Comprehensive and longitudinal multiomics analysis of PDX tumors, integrating RNA and exome sequencing, SNP arrays, and histopathology, demonstrated that tumors retain their molecular subtype, and transcriptomic and genomic profiles across anatomical sites. No evidence of emerging ITH or subtype transitions was observed, regardless of the microenvironment. The transcriptomic adaptations observed in metastases and different primary tumor sites are limited and are associated primarily with hypoxia, epithelial-mesenchymal transition (EMT), and invasion. Conclusions Our results suggest that invasive bladder cancers have a strong intrinsic tumor identity that is not easily reprogrammed by the microenvironment.