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Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients
Annika Fendler1,2,3,4, Daniel Bauer1, Jonas Busch2,3
1Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany.
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.
Insights
Researchers identified cancer stem cells (CSCs) in clear cell renal cell cancer (ccRCC) that drive tumor growth and metastasis. Targeting WNT and NOTCH signaling in these CSCs offers a promising strategy for developing new ccRCC treatments.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
Background:
- Clear cell renal cell cancer (ccRCC) treatments are limited, with high rates of metastatic progression.
- A cancer stem cell (CSC) population in ccRCC contributes to tumor aggressiveness and metastasis.
Purpose of the Study:
- To identify and characterize CSCs in ccRCC.
- To investigate the role of WNT and NOTCH signaling in ccRCC CSCs.
- To develop novel therapeutic strategies targeting ccRCC CSCs.
Main Methods:
- Transcriptional profiling and single-cell sequencing to characterize ccRCC CSCs.
- Establishment of non-adherent sphere cultures, 3D tumor organoids, and patient-derived xenografts.
- Inhibition of WNT and NOTCH signaling pathways.
Main Results:
- CSCs in ccRCC are quantitatively correlated with tumor aggressiveness and metastasis.
- Activated WNT and NOTCH signaling pathways were identified in ccRCC CSCs.
- WNT and NOTCH inhibitors reduced CSC proliferation and self-renewal in vitro and impaired tumor growth in vivo.
Conclusions:
- Targeting WNT and NOTCH signaling in ccRCC CSCs is a potential therapeutic strategy.
- The developed model systems (sphere cultures, organoids, xenografts) accurately reflect the in vivo situation.
- This approach holds promise for developing personalized treatments for ccRCC patients.
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