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

Zhe Ying, Madeline Sandoval, Slobodan Beronja

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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 the 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 the differentiation and cell cycle exit of epidermal progenitors. As a result, oncogenic PI3K–AKT-activated epidermis exhibits a growth disadvantage even though its cells are more proliferative. We then sought to uncover the underlying mechanism behind oncogene-induced differentiation via a series of genetic screens in vivo. An AKT substrate, SH3RF1, is identified 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.

Original languageEnglish
Pages (from-to)1256-1266
Number of pages11
JournalNature Cell Biology
Issue number11
StatePublished - 1 Nov 2018
Externally publishedYes


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