TY - JOUR
T1 - Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth
AU - Ying, Zhe
AU - Sandoval, Madeline
AU - Beronja, Slobodan
N1 - Funding Information:
The authors thank the following: W. Phillips for sharing the inducible Pik3caH1047R mouse model; V. Greco and C. Pineda for sharing the photoactivatable mouse model and the intravital imaging technique; M. Schober and A. Hsieh for critical reading of the manuscript; the Comparative Medicine Department (AAALAC-accredited; R. Uthamanthil, Director) for care of the mice in accordance with National Institutes of Health (NIH) guidelines; the Genomics Department (J. Delrow, Director) for sequencing; the Scientific Imaging Department (J. Vazquez, Director) for advice; and the Flow Cytometry Department (A. Berger, Director) for flow cytometry and FACS. This research was supported by grants from the NIH (R01-AR070780 to S.B.), a Cell & Molecular Biology Training Grant (to M.S.), and a Thomsen Family Fellowship (to Z.Y.). The authors dedicate this work to X. Chen, and are grateful for her strength and support.
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055426538&partnerID=8YFLogxK
U2 - 10.1038/s41556-018-0218-9
DO - 10.1038/s41556-018-0218-9
M3 - Article
C2 - 30361695
AN - SCOPUS:85055426538
SN - 1465-7392
VL - 20
SP - 1256
EP - 1266
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 11
ER -