Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression
Histologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for their biological differences. Here we show using single cell analysis that HVs harbor a tumor cell state characterized by expression of MUC16 (CA125), MUC4, and KRT24. This cell state is enriched in metastases, predicted to be highly resistant to chemotherapy, and linked with poor survival. We also find enriched expression of TM4SF1, a transmembrane protein, in HV tumor cells. Chimeric antigen receptor (CAR) T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in a TM4SF1 expression-dependent manner, highlighting its potential as a therapeutic target.
Authors
- Timothy Gilpatrick
- Maxwell V. Meng (ORCID: https://orcid.org/0009-0007-8838-8212)
- Hanbing Song (ORCID: https://orcid.org/0000-0002-2164-8813)
- Corynn Kasap (ORCID: https://orcid.org/0000-0002-3667-8097)
- Jonathan Chou (ORCID: https://orcid.org/0000-0003-1258-0391)
- Keliana Hui
- Paul Allegakoen
- Chien‐Kuang Cornelia Ding (ORCID: https://orcid.org/0000-0001-9047-0222)
- Kevin Chang (ORCID: https://orcid.org/0000-0002-6555-3592)
- Bradley A. Stohr (ORCID: https://orcid.org/0000-0002-5836-2624)
- Heiko Yang (ORCID: https://orcid.org/0000-0002-1278-0150)
- Sima P. Porten (ORCID: https://orcid.org/0000-0002-3948-4968)
- Arun P. Wiita (ORCID: https://orcid.org/0000-0002-7465-6964)
- Vipul Kumar (ORCID: https://orcid.org/0000-0001-7578-7467)
- Franklin W. Huang (ORCID: https://orcid.org/0000-0001-5447-0436)
- Kevin Lu (ORCID: https://orcid.org/0000-0003-2677-9537)
- Elizabeth Yip
- J. Gayle
- Julia H Pham
Institutions
- San Francisco VA Medical Center (US)
- University of California, Santa Barbara (US)
- University of California, San Francisco (US)
- Chan Zuckerberg Initiative (United States) (US)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1038/s41467-025-59888-8
- Citations
- 6
- Primary Topic
- Bladder and Urothelial Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 12.04
Funders
- California Urology Foundation
- Urology Foundation
- University of California, San Francisco
- Department of Medicine, University of California, San Francisco