Abstract

Hair follicles (HFs) form during development through reciprocal Wnt and Sonic Hedgehog (SHH) signals communicated between follicular germ and underlying dermal papilla (DP) cells. Although HFs typically only form during development, benign follicular tumors (BFTs) recapitulate embryonic-like HFs. By contrast, basal cell carcinoma (BCC) is a tumor caused by mutations that reprogram epithelial cells into an undifferentiated embryonic HF state that lacks an associated DP population. BFTs and BCCs share some common molecular and morphological features, providing a model to assess: 1) molecular pathways that can promote adult de novo HF regeneration and 2) how oncogenic mutations exploit these pathways to cause unchecked growth. We hypothesize that BFTs grow through reciprocal epithelial and dermal SHH and Wnt activation, while BCCs are caused by epithelial SHH-activating mutations but lack reciprocal dermal SHH and Wnt activation, and consequently, lack an associated DP population. Using immunofluorescence and quantitative multiplexed RNA fluorescence in situ hybridization (FISH), we measured protein and mRNA expression levels of markers of Wnt (LEF1) and SHH (PTCH1) signaling in BFTs and BCCs. All BFTs examined showed high SHH and Wnt activation in epithelial and underlying dermal cells, which corresponded with low epithelial proliferation and differentiation toward HF. By contrast, all BCCs showed high proliferation and uniform high SHH levels, while Wnt was low throughout the tumor. These markers were not detected in the dermis of BCCs, corresponding with a lack of DP cells. To identify a mechanism for dermal SHH activation and DP induction in BFTs, we show that the diffusible SHH ligand, which activates SHH signaling, was expressed in epithelial cells of BFTs but absent in BCCs. This quantitative analysis provides new insight into cell-cell interactions that promote benign neogenic HF growth and that can potentially suppress oncogenic growth.

Financial Disclosure: No current or relevant financial relationships exist.