RNAi screens in mice identify physiological regulators of oncogenic growth

Slobodan Beronja, Peter Janki, Evan Heller, Wen Hui Lien, Brice E. Keyes, Naoki Oshimori, Elaine Fuchs

Research output: Contribution to journalArticle

104 Scopus citations

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 (Hras G12V -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 Hras G12V -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.

Original languageEnglish (US)
Pages (from-to)185-190
Number of pages6
JournalNature
Volume501
Issue number7466
DOIs
StatePublished - Aug 15 2013

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    Beronja, S., Janki, P., Heller, E., Lien, W. H., Keyes, B. E., Oshimori, N., & Fuchs, E. (2013). RNAi screens in mice identify physiological regulators of oncogenic growth. Nature, 501(7466), 185-190. https://doi.org/10.1038/nature12464