Hedgehog-Wnt Interactions during Pathologic Epithelial Bud Development and Skin Tumorigenesis.

The Hedgehog (Hh) and canonical Wnt/beta-catenin signaling pathways are involved in various embryonic processes, and when aberrantly activated after birth in certain cell types or settings, are associated with the development of neoplasia. Although the Hh and Wnt pathways can be activated concurrently during tumorigenesis, the functional significance of signaling crosstalk in tumor initiation and progression has not been established. Constitutive 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/beta-catenin signaling. Similar to embryonic hair germs, human BCC buds exhibited increased levels of cytoplasmic and nuclear beta-catenin, a marker of canonical Wnt/beta-catenin signaling, and expressed early hair follicle lineage markers. We also detected canonical Wnt/beta-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, indicating pathologic Hh signaling brings about these changes indirectly, via canonical Wnt/beta-catenin pathway. My findings uncover a previously unknown requirement for ligand-driven, canonical Wnt/beta-catenin signaling for Hh-driven tumorigenesis, identify Wnt ligands as potential pharmacological target for these neoplasms, and establish the molecular basis for the well-known similarity between early BCCs and embryonic hair germs. I also describe my preliminary findings showing that epithelium-specific activation of Hh signaling is sufficient to reactivate growth of resting hair follicles, a process which is normally controlled by the Wnt/beta-catenin pathway. In addition, I show that epithelial Hh signaling leads to robust activation of melanogenesis, and this can be blocked by inhibiting Wnt ligand function with Dkk1. Taken together, these studies establish that a variety of responses to deregulated Hh signaling in skin, involving both epithelial cells and melanocytes, are strictly dependent on canonical Wnt/beta-catenin signaling. Moreover, they set the stage for studies further examining the biology and molecular basis of Hh-Wnt crosstalk in skin, and its potential relevance in other neoplasms.PhDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/75879/1/hoseongy_1.pd