RNAi screens in mice identify physiological regulators of oncogenic growth

Slobodan Beronja, Peter Janki, Evan Heller, Wen-Hui Lien, Brice E. Keyes, Naoki Oshimori and Elaine Fuchs ()
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Slobodan Beronja: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University
Peter Janki: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University
Evan Heller: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University
Wen-Hui Lien: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University
Brice E. Keyes: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University
Naoki Oshimori: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University
Elaine Fuchs: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University

Nature, 2013, vol. 501, issue 7466, 185-190

Abstract: Abstract Tissue growth is the multifaceted outcome of a cell’s intrinsic capabilities and its interactions with the surrounding environment. Decoding these complexities is essential for understanding human development and tumorigenesis. Here we tackle this problem by carrying out the first genome-wide RNA-interference-mediated screens in mice. Focusing on skin development and oncogenic (HrasG12V-induced) hyperplasia, our screens uncover previously unknown as well as anticipated regulators of embryonic epidermal growth. Among the top oncogenic screen hits are Mllt6 and the Wnt effector β-catenin, which maintain HrasG12V-dependent hyperproliferation. We also expose β-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion. Finally, we validate functional significance in mouse and human cancers, thereby establishing the feasibility of in vivo mammalian genome-wide investigations to dissect tissue development and tumorigenesis. By documenting some oncogenic growth regulators, we pave the way for future investigations of other hits and raise promise for unearthing new targets for cancer therapies.

Date: 2013
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DOI: 10.1038/nature12464

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