Bladder cancer evolution reveals early founders, polyclonal spread and subtype-specific aggressiveness

A multi-omics analysis of lethal metastatic bladder cancer from a rapid-autopsy program shows metastasis-to-metastasis seeding as the dominant spread pattern and polyclonal migration linked to worse survival. Histology-driven differences include early founder alterations in plasmacytoid and neuroendocrine variants, with cisplatin resistance in plasmacytoid tumors associated with Fanconi anaemia pathway activity. Single-nucleus RNA sequencing reveals substantial transcriptional and microenvironmental heterogeneity across subtypes, while post-mortem cfDNA captures the majority of driver alterations, offering a noninvasive readout of tumor identity and aggressiveness to guide therapy.