Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression
PMCID: PMC12174346
PMID: 40527915
DOI: 10.1038/s41467-025-59888-8
Journal: Nature communications
Publication Date: 2025-6-17
Authors: Yang H, Song H, Yip E, Gilpatrick T, Chang K, et al.
Key Points
- HV bladder cancers harbor a unique tumor cell state with distinct molecular characteristics, primarily expressing CA125, MUC4, and KRT24
- CA125+ cells were present in 13/14 HV tumors, compared to rare occurrence in high-grade UC (1/11) or carcinoma in situ (1/9)
- TM4SF1-targeted CAR T cells demonstrate promising therapeutic potential for treating aggressive bladder cancer variants
Summary
This single-cell RNA sequencing study investigated the molecular characteristics of histologic variant (HV) bladder cancers, a clinically aggressive subtype with limited understanding. By analyzing tumor epithelial cells from 11 HV and 4 conventional urothelial carcinoma (UC) specimens, researchers identified a distinct tumor cell state (Cluster 13) characterized by unique gene expression, including MUC16 (CA125), MUC4, and KRT24.
The study revealed that this cell state is predominantly found in HV tumors, is enriched in metastases, and is predicted to be highly chemotherapy-resistant. Notably, the researchers discovered TM4SF1 as a promising therapeutic target, demonstrating that chimeric antigen receptor (CAR) T cells engineered against this protein showed significant anti-tumor activity in both in vitro and in vivo models. Patients with HV tumors exhibited higher serum CA125 levels, suggesting potential diagnostic and prognostic implications.