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

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Item Type:Article
Title:Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients
Creators Name:Fendler, A. and Bauer, D. and Busch, J. and Jung, K. and Wulf-Goldenberg, A. and Kunz, S. and Song, K. and Myszczyszyn, A. and Elezkurtaj, S. and Erguen, B. and Jung, S. and Chen, W. and Birchmeier, W.
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.
Keywords:3-Ring Heterocyclic Compounds, Antineoplastic Agents, Cell Proliferation, Cellular Spheroids, Heterocyclic Bridged Bicyclo Compounds, Kidney, Kidney Neoplasms, Neoplastic Stem Cells, Notch Receptors, Primary Cell Culture, Pyrimidinones, Renal Cell Carcinoma, Signal Transduction, Single-Cell Analysis, Small Interfering RNA, Tumor Cell Line, Wnt Proteins, Xenograft Model Antitumor Assays, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:929
Date:17 February 2020
Official Publication:https://doi.org/10.1038/s41467-020-14700-7
PubMed:View item in PubMed

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