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Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation

Nature Cell Biology volume 14, pages 12821294 (2012) | Download Citation

Abstract

Basal cell carcinoma, the most frequent human skin cancer, arises from activating hedgehog (HH) pathway mutations; however, little is known about the temporal changes that occur in tumour-initiating cells from the first oncogenic hit to the development of invasive cancer. Using an inducible mouse model enabling the expression of a constitutively active Smoothened mutant (SmoM2) in the adult epidermis, we carried out transcriptional profiling of SmoM2-expressing cells at different times during cancer initiation. We found that tumour-initiating cells are massively reprogrammed into a fate resembling that of embryonic hair follicle progenitors (EHFPs). Wnt/ β-catenin signalling was very rapidly activated following SmoM2 expression in adult epidermis and coincided with the expression of EHFP markers. Deletion of β-catenin in adult SmoM2-expressing cells prevents EHFP reprogramming and tumour initiation. Finally, human basal cell carcinomas also express genes of the Wnt signalling and EHFP signatures.

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Acknowledgements

We would like to thank those who provided us with reagents and who are acknowledged in the text. C.B. is an investigator of WELBIO. C.B. is a chercheur qualifié, S.B. is a chargé de recherche and G.L. is a collaborateur scientifique of the FRS/FNRS; K.K.Y. is supported by TELEVIE. This work was supported by the FNRS, the program d’excellence CIBLES of the Wallonia Region, a research grant from the Fondation Contre le Cancer, the Fondation ULB, the Fond Yvonne Boël and the Fond Gaston Ithier, a starting grant of the European Research Council (ERC) and the EMBO Young Investigator Program.

Author information

Affiliations

  1. IRIBHM, Université Libre de Bruxelles (ULB), 808 route de Lennik, 1070 Brussels, Belgium

    • Khalil Kass Youssef
    • , Gaëlle Lapouge
    • , Karine Bouvrée
    • , Sylvain Brohée
    • , Ornella Appelstein
    • , Jean-Christophe Larsimont
    • , Vijayakumar Sukumaran
    • , Doriana Pucci
    • , Sophie Dekoninck
    •  & Cédric Blanpain
  2. Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium

    • Sandrine Rorive
    •  & Isabelle Salmon
  3. DIAPATH — Center for Microscopy and Molecular Imaging (CMMI), Gosselies 6041,Belgium

    • Sandrine Rorive
    •  & Isabelle Salmon
  4. Computer Science Department, Université Libre de Bruxelles, Boulevard du Triomphe, CP 212, 1050 Brussels, Belgium

    • Sylvain Brohée
    •  & Ornella Appelstein
  5. Laboratory of Computational Biology, Center for Human Genetics, K.U. Leuven, Leuven 3000, Belgium

    • Bram Van de Sande
    •  & Stein Aerts
  6. Department of Plastic Surgery, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070,Belgium

    • Jean-Valery Berthe
  7. Department of Dermatology, Erasme Hospital, 1070 Brussels, Belgium

    • Véronique del Marmol
  8. WELBIO, Université Libre de Bruxelles (ULB), 808 route de Lennik, 1070 Brussels, Belgium

    • Cédric Blanpain

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Contributions

C.B. and K.K.Y. designed the experiments and carried out the data analysis; K.K.Y., G.L., K.B., O.A., J.C.L., V.S., B.V.S., S.D., S.A. and D.P. carried out most of the experiments; S.B. carried out bioinformatic analysis of the microarray; S.R. and I.S. carried out immunohistochemistry analysis on human BCCs; J.V.B. and V.D.M. provided human biopsy materials; C.B. and K.K.Y. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Cédric Blanpain.

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DOI

https://doi.org/10.1038/ncb2628

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