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

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 and Walter Birchmeier ()
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Annika Fendler: Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association
Daniel Bauer: Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association
Jonas Busch: Berlin Institute of Health (BIH)
Klaus Jung: Charité-University Medicine
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)
Walter Birchmeier: Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14700-7

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