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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 1282–1294 (2012)Cite this article

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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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Figure 1: Transcriptional analysis of FACS-isolated SmoM2-expressing cells at different times following oncogene expression.
Figure 2: Reprogramming of adult interfollicular cells into EHFPs following SmoM2 expression.
Figure 3: Reprogramming of adult interfollicular cells into EHFPs following Ptch1 deletion from the hairless paw epidermis.
Figure 4: Wnt/ β-catenin signalling is rapidly activated in adult interfollicular cells following SmoM2 expression.
Figure 5: SmoM2 expression in embryonic epidermis accelerates BCC formation and promotes Wnt/ β-catenin signalling activation in the epidermis and its underlying dermis.
Figure 6: Cell-autonomous functions of Wnt/ β-catenin during SmoM2-induced embryonic hair follicle reprogramming.
Figure 7: Cell-autonomous role of Wnt/ β-catenin in SmoM2-induced tumorigenesis and pharmacological inhibition of tumour initiation in the adult epidermis.
Figure 8: Human BCCs express markers of the Wnt/ β-catenin and EHFP signatures.

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References

  1. Epstein, E. H. Basal cell carcinomas: attack of the hedgehog. Nat. Rev. Cancer 8, 743–754 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 3, 903–911 (2003).

    Article  PubMed  Google Scholar 

  3. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90–92 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171–10178 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat. Cell Biol. 12, 299–305 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Wong, S. Y. & Reiter, J. F. Wounding mobilizes hair follicle stem cells to form tumors. Proc. Natl Acad. Sci. USA 108, 4093–4098 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shirahama, S., Furukawa, F., Wakita, H. & Takigawa, M. E- and P-cadherin expression in tumor tissues and soluble E-cadherin levels in sera of patients with skin cancer. J. Dermatol. Sci. 13, 30–36 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Yoshikawa, K., Katagata, Y. & Kondo, S. Biochemical and immunohistochemical analyses of keratin expression in basal cell carcinoma. J. Dermatol. Sci. 17, 15–23 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Markey, A. C., Lane, E. B., Macdonald, D. M. & Leigh, I. M. Keratin expression in basal cell carcinomas. Br. J. Dermatol. 126, 154–160 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Vidal, V. P. et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr. Biol. 15, 1340–1351 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Vidal, V. P., Ortonne, N. & Schedl, A. SOX9 expression is a general marker of basal cell carcinoma and adnexal-related neoplasms. J. Cutan. Pathol. 35, 373–379 (2008).

    Article  PubMed  Google Scholar 

  12. Tanese, K. et al. G-protein-coupled receptor GPR49 is up-regulated in basal cell carcinoma and promotes cell proliferation and tumor formation. Am. J. Pathol. 173, 835–843 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang, S. H. et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/ β3-catenin signaling. Nat. Genet. 40, 1130–1135 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Rhee, H., Polak, L. & Fuchs, E. Lhx2 maintains stem cell character in hair follicles. Science 312, 1946–1949 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Osorio, K. M. et al. Runx1 modulates developmental, but not injury-driven, hair follicle stem cell activation. Development 135, 1059–1068 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Osorio, K. M., Lilja, K. C. & Tumbar, T. Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments. J. Cell Biol. 193, 235–250 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ellis, T. et al. The transcriptional repressor CDP (Cutl1) is essential for epithelial cell differentiation of the lung and the hair follicle. Genes Dev. 15, 2307–2319 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, G. Y., Wang, J., Mancianti, M. L. & Epstein, E. H. Jr Basal cell carcinomas arise from hair follicle stem cells in Ptch1(+/-) mice. Cancer Cell 19, 114–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kasper, M. et al. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc. Natl Acad. Sci. USA 108, 4099–4104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Uhmann, A. et al. The Hedgehog receptor Patched controls lymphoid lineage commitment. Blood 110, 1814–1823 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Lowry, W. E. et al. Defining the impact of β-catenin/Tcf transactivation on epithelial stem cells. Genes Dev. 19, 1596–1611 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. DasGupta, R. & Fuchs, E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557–4568 (1999).

    CAS  PubMed  Google Scholar 

  25. Enshell-Seijffers, D., Lindon, C., Kashiwagi, M. & Morgan, B. A. β-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair. Dev. Cell 18, 633–642 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rendl, M., Lewis, L. & Fuchs, E. Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS Biol. 3, e331 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Maretto, S. et al. Mapping Wnt/ β-catenin signaling during mouse development and in colorectal tumors. Proc. Natl Acad. Sci. USA 100, 3299–3304 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nat. Biotechnol. 22, 411–417 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO J. 18, 5931–5942 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vasioukhin, V., Bauer, C., Degenstein, L., Wise, B. & Fuchs, E. Hyperproliferation and defects in epithelial polarity upon conditional ablation of α-catenin in skin. Cell 104, 605–617 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Grachtchouk, V. et al. The magnitude of hedgehog signaling activity defines skin tumor phenotype. EMBO J. 22, 2741–2751 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Andl, T., Reddy, S. T., Gaddapara, T. & Millar, S. E. WNT signals are required for the initiation of hair follicle development. Dev. Cell 2, 643–653 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Enshell-Seijffers, D., Lindon, C., Wu, E., Taketo, M. M. & Morgan, B. A. β-catenin activity in the dermal papilla of the hair follicle regulates pigment-type switching. Proc. Natl Acad. Sci. USA 107, 21564–21569 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Collins, C. A., Kretzschmar, K. & Watt, F. M. Reprogramming adult dermis to a neonatal state through epidermal activation of β-catenin. Development 138, 5189–5199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Crowson, A. N. Basal cell carcinoma: biology, morphology and clinical implications. Mod. Pathol. 19 (Suppl 2), S127–S147 (2006).

    Article  PubMed  Google Scholar 

  38. El-Bahrawy, M., El-Masry, N., Alison, M., Poulsom, R. & Fallowfield, M. Expression of β-catenin in basal cell carcinoma. Br. J. Dermatol. 148, 964–970 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Saldanha, G., Ghura, V., Potter, L. & Fletcher, A. Nuclear β-catenin in basal cell carcinoma correlates with increased proliferation. Br. J. Dermatol. 151, 157–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Kriegl, L., Horst, D., Kirchner, T. & Jung, A. LEF-1 expression in basal cell carcinomas. Br. J. Dermatol. 160, 1353–1356 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Wong, D. J. et al. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2, 333–344 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499–507 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, J. et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313–324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95, 605–614 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Silva-Vargas, V. et al. β-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev. Cell 9, 121–131 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Zhang, Y. et al. Activation of {β}-catenin signaling programs embryonic epidermis to hair follicle fate. Development 135, 2161–2172 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Krahl, D. & Sellheyer, K. Basal cell carcinoma and pilomatrixoma mirror human follicular embryogenesis as reflected by their differential expression patterns of SOX9 and β-catenin. Br. J. Dermatol. 162, 1294–1301 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Vasioukhin, V., Degenstein, L., Wise, B. & Fuchs, E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl Acad. Sci. USA 96, 8551–8556 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Means, A. L., Xu, Y., Zhao, A., Ray, K. C. & Gu, G. A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis 46, 318–323 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  52. McCall, M. N., Bolstad, B. M. & Irizarry, R. A. Frozen robust multiarray analysis (fRMA). Biostatistics 11, 242–253 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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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.

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Authors and 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.

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Correspondence to Cédric Blanpain.

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Youssef, K., Lapouge, G., Bouvrée, K. et al. Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation. Nat Cell Biol 14, 1282–1294 (2012). https://doi.org/10.1038/ncb2628

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