256 Non-canonical control of hedgehog signaling in skin basal cell carcinoma

Basal cell carcinoma (BCC) is the most common cancer in United States, affecting up to four million Americans annually. BCC caused by mutations Hedgehog (HH) pathway, leading activation of receptor smoothened (SMO) and GLI transcription factors. SMO a G-protein coupled (GPCR), canonically signaling independent pathways. However, we have previously found non-canonical Gα protein-dependent pathway regulating HH signaling. In mouse skin, inactivating Gαs or its downstream target protein kinase A (PKA) blocks basal differentiation triggers formation. Remarkably, PKA disruption sufficient activate GLI. this study used bulk single-cell RNA sequencing compare tumors arising from canonical activation. Canonical formation was initiated expressing constitutive active form (SMOM2), while triggered knockout gene (GnasKO) inhibitor (PKI) expression. Analysis expression profiles these models indicated significant overlap differentially regulated genes. Furthermore, GnasKO SMOM2 mice showed 70% were almost indistinguishable principal component analysis (PCA). Common genes among enrichment for targets BCC-related Single-cell tail skin remarkable parallel signatures, with tumor cells different clustering together graph-based analysis. Overall, our results indicate that share similar profiles, supporting idea mammalian depends on inactivation drive We are currently dissecting mechanisms determine crosstalk between signaling, which could provide novel druggable treatment.