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


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.


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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).

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