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

Steven Hoseong Yang, Thomas Andl, Vladimir Grachtchouk, Aiqin Wang, Jianhong Liu, Li Jyun Syu, Jenny Ferris, Timothy S. Wang, Adam B. Glick, Sarah E. Millar, Andrzej A. Dlugosz

Research output: Contribution to journalArticle

148 Scopus citations

Abstract

Constitutive Hedgehog (Hh) signaling underlies several human tumors, including basal cell carcinoma (BCC) and basaloid follicular hamartoma in skin. Intriguingly, superficial BCCs arise as de novo epithelial buds resembling embryonic hair germs, collections of epidermal cells whose development is regulated by canonical Wnt/β-catenin signaling. 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, M2SMO, 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.

Original languageEnglish (US)
Pages (from-to)1130-1135
Number of pages6
JournalNature Genetics
Volume40
Issue number9
DOIs
StatePublished - Sep 1 2008

All Science Journal Classification (ASJC) codes

  • Genetics

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    Hoseong Yang, S., Andl, T., Grachtchouk, V., Wang, A., Liu, J., Syu, L. J., Ferris, J., Wang, T. S., Glick, A. B., Millar, S. E., & Dlugosz, A. A. (2008). Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/β-catenin signaling. Nature Genetics, 40(9), 1130-1135. https://doi.org/10.1038/ng.192