Dissection of Gαs and Hedgehog signaling crosstalk reveals therapeutic opportunities to target adenosine receptor 2b in Hedgehog-dependent tumors.

Basal cell carcinoma (BCC), the most common human cancer, is driven by hyperactivation of Hedgehog Smoothened (SMO) and GLI transcription. Gαs and protein kinase A (PKA) negatively regulate Hedgehog signaling, offering an alternative BCC development and treatment pathway. Here, using histology alongside bulk and single-cell RNA sequencing, we find that mouse BCC-like tumors that originate from Gαs pathway inactivation are strikingly similar to those driven by canonical Hedgehog SMO.