Constitutive Hedgehog (Hh) signaling underlies several human tumors¹, including basal cell carcinoma (BCC) and basaloid follicular hamartoma in skin^{2, 3}. Intriguingly, superficial BCCs arise as de novo epithelial buds resembling embryonic hair germs^{4, 5, 6}, collections of epidermal cells whose development is regulated by canonical Wnt/-catenin signaling^{7, 8}. Similar to embryonic hair germs, human BCC buds showed increased levels of cytoplasmic and nuclear -catenin and expressed early hair follicle lineage markers. We also detected canonical Wnt/-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/-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.

1. Department of Dermatology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA.
2. Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA.
3. Departments of Dermatology and Cell and Developmental Biology, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
4. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
5. Present addresses: Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37232, USA (T.A.) Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, New York 14263, USA (V.G.).

Correspondence to: Andrzej A Dlugosz^1,2 e-mail: dlugosza@umich.edu

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