Dissection of Gas and Hedgehog Signaling Crosstalk Reveals Therapeutic Opportunities to Target Hedgehog-Dependent Tumors.

Abstract

Basal cell carcinoma (BCC), the most common human cancer, is driven by hyperactivation of the Hedgehog pathway mediated by Smoothened (SMO) signaling and GLI transcription. Gas and protein kinase A (PKA) negatively regulate Hedgehog signaling, offering a potential alternative BCC development and treatment pathway. Here, using histology alongside bulk and single-cell RNA sequencing, we found that mouse BCC-like tumors that originate from Gas pathway inactivation are highly similar to those driven by canonical Hedgehog signaling induced by constitutive SMO activation. Both pathways led to expansion of basal stem cells in the skin, with tumor cells clustering in two distinct populations with markers for touch-dome and isthmus stem cell-like cells. Interestingly, mutations that reduce Gas and PKA activity were present in human BCC. Tumors from Gas pathway inactivation were independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as SMO-independent oncogenic Hedgehog signaling models. Finally, activation of the Gas-coupled adenosine 2B receptor with BAY60-6583 counteracted oncogenic SMO, reducing Hedgehog signaling and tumor growth. Together, these findings offer a potential therapeutic strategy for BCC.

View details for DOI 10.1158/0008-5472.CAN-25-1109

View details for PubMedID 41460725