Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression

Heiko Yang, Hanbing Song, Elizabeth Yip, Timothy Gilpatrick, Kevin Chang, Paul Allegakoen, Kevin L. Lu, Keliana Hui, Julia H. Pham, Corynn Kasap, Vipul Kumar, Janae Gayle, Bradley A. Stohr, Chien-Kuang Cornelia Ding, Arun P. Wiita, Maxwell V. Meng, Jonathan Chou, Sima P. Porten and Franklin W. Huang ()
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Heiko Yang: University of California San Francisco
Hanbing Song: University of California San Francisco
Elizabeth Yip: University of California San Francisco
Timothy Gilpatrick: University of California San Francisco
Kevin Chang: University of California San Francisco
Paul Allegakoen: University of California San Francisco
Kevin L. Lu: University of California San Francisco
Keliana Hui: University of California San Francisco
Julia H. Pham: University of California San Francisco
Corynn Kasap: University of California San Francisco
Vipul Kumar: University of California San Francisco
Janae Gayle: University of California San Francisco
Bradley A. Stohr: University of California San Francisco
Chien-Kuang Cornelia Ding: University of California San Francisco
Arun P. Wiita: University of California San Francisco
Maxwell V. Meng: University of California San Francisco
Jonathan Chou: University of California San Francisco
Sima P. Porten: University of California San Francisco
Franklin W. Huang: University of California San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59888-8

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