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; Franklin W Huang

doi:10.1038/s41467-025-59888-8

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

Nat Commun. 2025 Jun 17;16(1):5312. doi: 10.1038/s41467-025-59888-8.

Authors

Heiko Yang^#^{1

2}, Hanbing Song^#³, Elizabeth Yip³, Timothy Gilpatrick⁴, Kevin Chang^{1

3}, Paul Allegakoen³, Kevin L Lu⁴, Keliana Hui³, Julia H Pham³, Corynn Kasap³, Vipul Kumar³, Janae Gayle^{3

5}, Bradley A Stohr⁴, Chien-Kuang Cornelia Ding⁴, Arun P Wiita⁶, Maxwell V Meng¹, Jonathan Chou³, Sima P Porten¹, Franklin W Huang^{7

8

9

10

11

12}

Affiliations

¹ Department of Urology, University of California San Francisco, San Francisco, CA, USA.
² Division of Urology, Department of Surgery, University of Colorado, Aurora, CO, USA.
³ Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
⁵ College of Letters and Science, University of California Santa Barbara, Santa Barbara, CA, USA.
⁶ Department of Laboratory Medicine, University of California San Francisco, San Francisco, USA.
⁷ Department of Urology, University of California San Francisco, San Francisco, CA, USA. franklin.huang@ucsf.edu.
⁸ Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA. franklin.huang@ucsf.edu.
⁹ Chan Zuckerberg Biohub, San Francisco, CA, USA. franklin.huang@ucsf.edu.
¹⁰ Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA, USA. franklin.huang@ucsf.edu.
¹¹ Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA. franklin.huang@ucsf.edu.
¹² Division of Hematology and Oncology, Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA. franklin.huang@ucsf.edu.

^# Contributed equally.

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.

MeSH terms

Animals
Antigens, Surface
CA-125 Antigen* / genetics
CA-125 Antigen* / metabolism
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
Membrane Proteins* / genetics
Membrane Proteins* / metabolism
Mice
Mucin-4 / genetics
Mucin-4 / metabolism
Neoplasm Proteins* / genetics
Neoplasm Proteins* / metabolism
Single-Cell Analysis
Urinary Bladder Neoplasms* / genetics
Urinary Bladder Neoplasms* / metabolism
Urinary Bladder Neoplasms* / pathology
Urinary Bladder Neoplasms* / therapy
Xenograft Model Antitumor Assays

Substances

Membrane Proteins
CA-125 Antigen
TM4SF1 protein, human
MUC16 protein, human
Neoplasm Proteins
Mucin-4
Antigens, Surface