Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth

Oncogenic lesions are surprisingly common in morphologically and functionally normal human skin, however, the cellular and molecular mechanisms that suppress their cancer-driving potential to maintain tissue homeostasis are unknown. By employing assays for direct and quantitative assessment of cell fate choices in vivo, we show that oncogenic activation of PI3K/AKT, the most commonly activated oncogenic pathway in cancer, promotes differentiation and cell-cycle exit of epidermal progenitors. As a result, oncogenic PI3K/AKT activated epidermis exhibits growth disadvantage even though its cells are more proliferative. To uncover the underlying mechanism behind oncogene-induced differentiation, we conduct a series of genetic screens in vivo, and identify an AKT substrate SH3RF1 as a specific promoter of epidermal differentiation that has no effect on proliferation. Our study provides evidence for a direct, cell autonomous mechanism that can suppresses progenitor cell renewal and block clonal expansion of epidermal cells bearing a common and activating mutation in Pik3ca.