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Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients

Author

Listed:
  • Annika Fendler

    (Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association
    Berlin Institute of Health (BIH)
    Charité-University Medicine
    Berlin Institute for Urologic Research)

  • Daniel Bauer

    (Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association)

  • Jonas Busch

    (Berlin Institute of Health (BIH)
    Charité-University Medicine)

  • Klaus Jung

    (Charité-University Medicine
    Berlin Institute for Urologic Research)

  • Annika Wulf-Goldenberg

    (Experimental Pharmacology and Oncology GmbH (EPO))

  • Severine Kunz

    (Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association)

  • Kun Song

    (Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association)

  • Adam Myszczyszyn

    (Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association)

  • Sefer Elezkurtaj

    (Charité-University Medicine)

  • Bettina Erguen

    (Charité-University Medicine)

  • Simone Jung

    (Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association)

  • Wei Chen

    (Berlin Institute of Health (BIH)
    Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association
    Southern University of Science and Technology)

  • Walter Birchmeier

    (Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association
    Berlin Institute of Health (BIH))

Abstract

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients.

Suggested Citation

  • Annika Fendler & Daniel Bauer & Jonas Busch & Klaus Jung & Annika Wulf-Goldenberg & Severine Kunz & Kun Song & Adam Myszczyszyn & Sefer Elezkurtaj & Bettina Erguen & Simone Jung & Wei Chen & Walter Bi, 2020. "Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14700-7
    DOI: 10.1038/s41467-020-14700-7
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    Cited by:

    1. Yige Wu & Nadezhda V. Terekhanova & Wagma Caravan & Nataly Naser Al Deen & Preet Lal & Siqi Chen & Chia-Kuei Mo & Song Cao & Yize Li & Alla Karpova & Ruiyang Liu & Yanyan Zhao & Andrew Shinkle & Ilya , 2023. "Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    2. Huanhuan Cui & Hongyang Yi & Hongyu Bao & Ying Tan & Chi Tian & Xinyao Shi & Diwen Gan & Bin Zhang & Weizheng Liang & Rui Chen & Qionghua Zhu & Liang Fang & Xin Gao & Hongda Huang & Ruijun Tian & Silk, 2022. "The SWI/SNF chromatin remodeling factor DPF3 regulates metastasis of ccRCC by modulating TGF-β signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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