A single-cell atlas of bladder cancer unveils dynamic cellular composition and endothelial functional shifts during progression.

PURPOSE

Bladder cancer (BC) is characterized by high heterogeneity, with non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) stages differing significantly in clinical behavior and outcomes. The transition from NMIBC to MIBC involves extensive tumor microenvironment (TME) remodeling, particularly in endothelial cells (ECs), which drive angiogenesis and modulate immune and extracellular matrix (ECM) interactions. However, the precise roles of ECs in this progression remain poorly defined.

METHODS

Public single-cell RNA sequencing (scRNA-seq) datasets from 47 BC patients were analyzed to characterize endothelial cell heterogeneity and functional states across NMIBC and MIBC. Computational tools such as CellChat were applied to reconstruct cell-cell communication networks, focusing on pathways related to angiogenesis, immune crosstalk, and ECM remodeling.

RESULTS

Twelve major cell types were identified, with endothelial cells exhibiting distinct transcriptional profiles between NMIBC and MIBC. NMIBC-associated ECs promoted adhesion and migration through HMGB1 and CXCL12 signaling. In contrast, MIBC was enriched in an ADAM10 endothelial subset associated with vascular remodeling and activation of Wnt signaling via CTNNB1. Key ligand-receptor interactions highlighted the dynamic roles of ECs in TME modulation during BC progression.

CONCLUSIONS

This study reveals stage-specific endothelial cell phenotypes and signaling networks in BC. The identification of an MIBC-specific ADAM10 endothelial subset underscores its potential role in driving tumor progression and highlights opportunities for stage-adapted vascular-targeted therapies. These findings advance our understanding of BC pathogenesis and provide the foundation for novel therapeutic strategies.