Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

The progression of conventional urothelial carcinoma (UC) of the bladder to a tumor with a mesenchymal phenotype, referred to as sarcomatoid carcinoma (SARC), is signified by a high propensity for regional and distant metastasis resulting in shorter survival. We report a comprehensive retrospective analysis of 28 cases of SARCs and 84 cases of conventional UCs. A TCGA cohort of 408 muscle-invasive bladder cancers was used as a reference cohort. SARCs showed a distinct mutational landscape with enrichment of p53, PIK3CA, and RB1 mutations. They developed from basal precursor conventional UCs and could be divided into a basal subtype and the most aggressive mesenchymal subtype. Expression analysis showed that SARCs are driven by dysregulation of cell cycle and EMT regulatory networks and nearly half exhibited an immune infiltration phenotype with PDL1 upregulation. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.