1. École Polytechnique Fédérale de Lausanne (EPFL)/ISREC (Swiss Institute for Experimental Cancer Research) and National Center of Competence in Research (NCCR) 'Molecular Oncology', Chemin des Boveresses 155, 1066 Epalinges, Switzerland
2. Departamento de Bioquímica, Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
3. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), BP 10142, CU de Strasbourg, 67404 Illkirch, France
4. Laboratory of Cutaneous Biology, Dermatology CHUV and FBM UNIL, Avenue de Beaumont 29, 1011 Lausanne, Switzerland
5. Max Delbrück Centrum, Robert-Roessle-Strasse 10, 13122 Berlin, Germany

Correspondence to: Joerg Huelsken¹ Correspondence and requests for materials should be addressed to J.H. (Email: joerg.huelsken@epfl.ch).

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 -catenin signalling³ as being essential in sustaining the CSC phenotype. Ablation of the -catenin gene results in the loss of CSCs and complete tumour regression. In addition, we provide evidence for the involvement of increased -catenin signalling in malignant human squamous cell carcinomas. Because Wnt/-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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