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

Author

Listed:
  • Heiko Yang

    (University of California San Francisco
    University of Colorado)

  • 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
    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
    University of California Santa Barbara)

  • 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
    University of California San Francisco
    Chan Zuckerberg Biohub
    University of California San Francisco)

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.

Suggested Citation

  • 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, 2025. "Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59888-8
    DOI: 10.1038/s41467-025-59888-8
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    References listed on IDEAS

    as
    1. Vu N. Ngo & Ryan M. Young & Roland Schmitz & Sameer Jhavar & Wenming Xiao & Kian-Huat Lim & Holger Kohlhammer & Weihong Xu & Yandan Yang & Hong Zhao & Arthur L. Shaffer & Paul Romesser & George Wright, 2011. "Oncogenically active MYD88 mutations in human lymphoma," Nature, Nature, vol. 470(7332), pages 115-119, February.
    2. Hanbing Song & Hannah N. W. Weinstein & Paul Allegakoen & Marc H. Wadsworth & Jamie Xie & Heiko Yang & Ethan A. Castro & Kevin L. Lu & Bradley A. Stohr & Felix Y. Feng & Peter R. Carroll & Bruce Wang , 2022. "Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
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