Functional Roles of Wnt/β-catenin Pathway Components in Pre-Basal Cell Carcinoma-like Cell Proliferation and Survival

Wnt/β-catenin signaling supports basal cell carcinoma (BCC)-like tumor initiation in mice. However, nuclear β-catenin is frequently detected in well-developed BCCs and correlates with increased tumor cell proliferation, suggesting that Wnt/β-catenin signaling may also promote BCC development. Our analysis of published single-cell transcriptomic datasets from human BCCs revealed that multiple Wnt pathway components, including Wntless (WLS) and the Wnt receptor Frizzled2 (FZD2), are enriched in specific BCC cell populations with active Hedgehog (Hh) signaling. Using an inducible mouse model with forced epithelial expression of the Hh activator GLI2ΔN, we found that Wnt-responsive Axin2⁺ epidermal basal cells contribute to BCC-like tumor formation. Deletion of epithelial β-catenin or WLS several days after GLI2ΔN expression significantly reduced tumor cell proliferation without affecting BCC marker expression, Hh pathway activity, or apoptosis. These findings indicate that Wnt/β-catenin signaling acts downstream of Hh signaling to promote pre-BCC-like cell proliferation. Furthermore, Wnt receptor Fzd2 depletion reduced tumor cell proliferation and induced apoptosis, suggesting that FZD2 promotes proliferation and survival through β-catenin-dependent and -independent mechanisms. These findings identify Wnt pathway components as key regulators of pre-BCC-like cell proliferation and survival.