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Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling

Abstract

Continuous turnover of epithelia is ensured by the extensive self-renewal capacity of tissue-specific stem cells1. Similarly, epithelial tumour maintenance relies on cancer stem cells (CSCs), which co-opt stem cell properties2. For most tumours, the cellular origin of these CSCs and regulatory pathways essential for sustaining stemness have not been identified. In murine skin, follicular morphogenesis is driven by bulge stem cells that specifically express CD34. Here we identify a population of cells in early epidermal tumours characterized by phenotypic and functional similarities to normal bulge skin stem cells. This population contains CSCs, which are the only cells with tumour initiation properties. Transplants derived from these CSCs preserve the hierarchical organization of the primary tumour. We describe β-catenin signalling3 as being essential in sustaining the CSC phenotype. Ablation of the β-catenin gene results in the loss of CSCs and complete tumour regression. In addition, we provide evidence for the involvement of increased β-catenin signalling in malignant human squamous cell carcinomas. Because Wnt/β-catenin signalling is not essential for normal epidermal homeostasis, such a mechanistic difference may thus be targeted to eliminate CSCs4 and consequently eradicate squamous cell carcinomas.

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Figure 1: Skin cancers contain cells with bulge stem cell phenotype.
Figure 2: Cancer stem cells efficiently initiate secondary tumours that recapitulate the organization of the primary tumour.
Figure 3: β-Catenin signalling is essential to maintain skin tumorigenesis.
Figure 4: Functional importance of β-catenin signalling in human skin SCCs.

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Acknowledgements

We thank S. Duboux for assistance; A. Wilson and U. Koch for support and advice with FACS analysis; P. Dotto for suggestions during establishment of the transplantation model; D. Trono for lentiviruses; and I. Stamenkovich for counsel in skin pathologies. I.M., D.K. and J.H. were supported in part by the Swiss League against Cancer, the SNF and the Swiss NCCR in Molecular Oncology, and H.P. was supported by the Spanish Association for Cancer Fight (AECC). Work in Madrid was supported in part by the Spanish Ministry of Education and Science to A.C.

Author Contributions H.P., D.K. and T.H. performed research and analysed data; D.H. analysed data; A.C. designed research; D.M., P.C., M.H., D.H. and W.B. contributed vital reagents; I.M. and J.H. designed and performed research, analysed data, and wrote the paper.

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Correspondence to Joerg Huelsken.

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Malanchi, I., Peinado, H., Kassen, D. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452, 650–653 (2008). https://doi.org/10.1038/nature06835

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