Urothelial-to-Neural Lineage Plasticity Drives Progression to Small Cell Bladder Cancer

Small cell carcinoma (SCC) of the bladder displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive molecular analysis of 34 cases of SCC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 invasive conventional UC bladder cancers used as the reference. SCCs showed distinct mutational landscapes characterized by nearly uniform inactivation of TP53 and frequently combined TP53 and RB1 loss. SCCs are dominated by Sanger mutation signature 3 that is associated with loss of BRCA1/2 function in other solid tumors. SCC's are related to the basal molecular subtype of conventional UC but are characterized by downregulation of both luminal and basal markers with the retention of the stem cell marker CD44. Whole transcriptome analyses indicate that SCCs display lineage plasticity and are driven by urothelial-to-neural phenotypic switch in the background of a dysregulated EMT network. SCCs are depleted of immune cells, and the majority of them express relatively high levels of the immune checkpoint receptor, adenosine receptor A 2A (ADORA2A), which is known as a potent inhibitor of immune infiltration. Our observations have important implications for prognostication and the development of novel therapies for this highly lethal bladder cancer variant.