Inactivation of a Gαs-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis

Genomic alterations in GNAS, the gene coding for the G alpha(s) heterotrimeric G protein, are associated with a large number of human diseases. Here, we explored the role of G alpha(s) on stem cell fate decisions by using the mouse epidermis as a model system. Conditional epidermal deletion of Gnas or repression of PKA signalling caused a remarkable expansion of the stem cell compartment, resulting in rapid basal-cell carcinoma formation. In contrast, inducible expression of active G alpha(s) in the epidermis caused hair follicle stem cell exhaustion and hair loss. Mechanistically, we found that G alpha(s)-PKA disruption promotes the cell autonomous Sonic Hedgehog pathway stimulation and Hippo signalling inhibition, resulting in the non-canonical activation of GLI and YAP1. Our study highlights an important tumour suppressive function of G alpha(s)-PKA, limiting the proliferation of epithelial stem cells and maintaining proper hair follicle homeostasis. These findings could have broad implications in multiple pathophysiological conditions, including cancer.