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Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/β-catenin signaling

Abstract

Constitutive Hedgehog (Hh) signaling underlies several human tumors1, including basal cell carcinoma (BCC) and basaloid follicular hamartoma in skin2,3. Intriguingly, superficial BCCs arise as de novo epithelial buds resembling embryonic hair germs4,5,6, collections of epidermal cells whose development is regulated by canonical Wnt/β-catenin signaling7,8. Similar to embryonic hair germs, human BCC buds showed increased levels of cytoplasmic and nuclear β-catenin and expressed early hair follicle lineage markers. We also detected canonical Wnt/β-catenin signaling in epithelial buds and hamartomas from mice expressing an oncogene, M2SMO9, leading to constitutive Hh signaling in skin. Conditional overexpression of the Wnt pathway antagonist Dkk1 in M2SMO-expressing mice potently inhibited epithelial bud and hamartoma development without affecting Hh signaling. Our findings uncover a hitherto unknown requirement for ligand-driven, canonical Wnt/β-catenin signaling for Hh pathway-driven tumorigenesis, identify a new pharmacological target for these neoplasms and establish the molecular basis for the well-known similarity between early superficial BCCs and embryonic hair germs.

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Figure 1: Human superficial basal cell carcinoma (BCC) expresses hair bud lineage markers.
Figure 2: Ectopic Hh signaling in M2SMO-expressing hairless mouse skin drives superficial BCC-like downgrowths resembling hair buds.
Figure 3: Canonical Wnt signaling is activated in human superficial BCC and epithelial buds in M2SMO-expressing hairless mouse skin.
Figure 4: Inhibition of canonical Wnt signaling with Dkk1 blocks M2SMO-induced development of epithelial buds and follicular hamartomas.

References

  1. Rubin, L.L. & de Sauvage, F.J. Targeting the Hedgehog pathway in cancer. Nat. Rev. Drug Discov. 5, 1026–1033 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Daya-Grosjean, L. & Couve-Privat, S. Sonic hedgehog signaling in basal cell carcinomas. Cancer Lett. 225, 181–192 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Lever, W.F. Pathogenesis of benign tumors of cutaneous appendages and of basal cell epithelioma. Arch. Dermatol. Syph. 57, 709–724 (1948).

    Article  Google Scholar 

  5. Montgomery, H. Histogenesis of basal-cell epithelioma. Radiology 25, 8–23 (1935).

    Article  Google Scholar 

  6. Sellheyer, K. & Krahl, D. Basal cell (trichoblastic) carcinoma common expression pattern for epithelial cell adhesion molecule links basal cell carcinoma to early follicular embryogenesis, secondary hair germ, and outer root sheath of the vellus hair follicle: a clue to the adnexal nature of basal cell carcinoma? J. Am. Acad. Dermatol. 58, 158–167 (2008).

    Article  PubMed  Google Scholar 

  7. 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 

  8. 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 

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

    Article  CAS  PubMed  Google Scholar 

  10. Fuchs, E. Skin stem cells: rising to the surface. J. Cell Biol. 180, 273–284 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Chiang, C. et al. Essential role for sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Pasca di Magliano, M. et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS. ONE 2, e1155 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Taipale, J. & Beachy, P.A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Mullor, J.L., Dahmane, N., Sun, T. & Altaba, A. Wnt signals are targets and mediators of Gli function. Curr. Biol. 11, 769–773 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Yamazaki, F., Aragane, Y., Kawada, A. & Tezuka, T. Immunohistochemical detection for nuclear β-catenin in sporadic basal cell carcinoma. Br. J. Dermatol. 145, 771–777 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. 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 

  19. Li, X., Deng, W., Lobo-Ruppert, S.M. & Ruppert, J.M. Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin. Oncogene 26, 4489–4498 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. Lo Celso, C., Prowse, D.M. & Watt, F.M. Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 131, 1787–1799 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Ito, M. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Jih, D.M. et al. Familial basaloid follicular hamartoma: lesional characterization and review of the literature. Am. J. Dermatopathol. 25, 130–137 (2003).

    Article  PubMed  Google Scholar 

  24. Oseroff, A.R. et al. Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy. Arch. Dermatol. 141, 60–67 (2005).

    Article  PubMed  Google Scholar 

  25. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Chu, E.Y. et al. Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 131, 4819–4829 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Callahan, C.A. et al. MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev. 18, 2724–2729 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mao, B. et al. Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling. Nature 417, 664–667 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452, 650–653 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Braun, K.M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Pierre Coulombe for providing K17 rabbit polyclonal antibody and Henry Sun for providing AE13 and AE15 antibodies; Eric Fearon and Deb Gumucio for constructive comments on the manuscript; and members of the Dlugosz lab for valuable input on this project. This work was supported by NIH grants R01-AR45973 and R01-CA87837 (A.A.D.), T32-HD007505 and T32-GM07863 (S.H.Y.), and R01-AR47709 and R01-DE015342 (S.E.M.). For production of transgenic mice we acknowledge members of the Transgenic Animal Model Core of the University of Michigan's Biomedical Research Core Facilities, funded in part by P30-CA46592 (University of Michigan Cancer Center Core support).

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Experiments were designed by S.H.Y. and A.A.D. Tissue harvests, whole-mount analysis, semiquantitative RT-PCR and immunoblotting were performed by S.H.Y. T.S.W. performed collection of human BCC samples. Immunohistochemistry and immunofluorescence staining were carried out by S.H.Y. and A.W. Genotyping was performed by S.H.Y., A.W., J.L., L.-J.S. and J.F. M2SMO-expressing mice were initially generated by V.G. Animal maintenance and breeding were performed by S.H.Y., A.W., J.L. and J.F. TRE-Dkk1 mice were provided by T.A. and S.E.M., and K5-rtTA mice were provided by A.B.G. T.A. and S.E.M. participated in study design and discussion of the results. The manuscript was written by S.H.Y., with draft revisions by A.A.D. and input from S.E.M. and T.A.

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Correspondence to Andrzej A Dlugosz.

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Hoseong Yang, S., Andl, T., Grachtchouk, V. et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/β-catenin signaling. Nat Genet 40, 1130–1135 (2008). https://doi.org/10.1038/ng.192

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