snRNASeq of Metastatic Urothelial carcinoma samples

Using experimental models, we demonstrated that Fanconi Anemia pathway activity positively correlated with resistance to cisplatin chemotherapy, demonstrating a molecular basis for therapy resistance in plasmacytoid patients. We report the first single-nucleus profiling of mBLCA histological subtypes, revealing mixed cell states in plasmacytoid tumors and that increased overall transcriptional heterogeneity was associated with longer patient survival.

Characterization of the tumor microenvironment uncovered distinct patterns of immune activation across histological subtypes, with plasmacytoid tumors exhibiting an immune-inflamed profile, while squamous subtype was dominated by immunosuppressive interactions. Lastly, we demonstrated that post-mortem cell-free DNA captured both genomic heterogeneity and transcriptional activity of the subtypes, providing a potential strategy to non-invasively assess tumor identity and aggressiveness in patients with mBLCA.

Our results provide new principles into how tumor heterogeneity shapes the evolutionary history of cancer progression within subtypes of human bladder cancer