Cellular origins and etiological factors for squamous cell carcinoma and related cancer types of the bladder.

Squamous cell carcinoma (SCC) of the bladder is a rare disease with poor prognosis and limited molecular profiling. Here we present a multi-layer, comparative investigation on bladder SCC and related cancers, namely pure urothelial carcinoma (UC), UC with squamous differentiation, and bladder adenocarcinoma. The mutational signatures of SCC, UC with squamous differentiation, and pure UC imply similar etiologies, with APOBEC-derived signatures found in around a third of samples. SCC and UC with squamous differentiation both highly express basal/squamous markers, different from the luminal profile in UC. We have also dissected the tumor microenvironment and cell type-specific expression in primary tumor and lymph node metastases of SCC at single-cell resolution, and SCC tumor cells also exhibit high expression of basal/squamous markers compared with the luminal feature in UC and adenocarcinoma. Similar mutational signatures present at different contributing fractions, combined with distinct transcriptomic features in various types of bladder cancer, provide an interesting perspective on etiological factors and suggest tumor initiation from potentially different urothelial cell types. The molecular landscape of SCC and related bladder cancers presented in this study improves our understanding of their etiologies and possible cellular origins, and may facilitate future prevention strategies and therapy development. © 2026 The Pathological Society of Great Britain and Ireland.