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RNAi screens in mice identify physiological regulators of oncogenic growth

Author

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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)

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.

Suggested Citation

  • Slobodan Beronja & Peter Janki & Evan Heller & Wen-Hui Lien & Brice E. Keyes & Naoki Oshimori & Elaine Fuchs, 2013. "RNAi screens in mice identify physiological regulators of oncogenic growth," Nature, Nature, vol. 501(7466), pages 185-190, September.
    • Handle: RePEc:nat:nature:v:501:y:2013:i:7466:d:10.1038_nature12464
    DOI: 10.1038/nature12464
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    Cited by:

    1. Anthony Veltri & Christopher M. R. Lang & Gaia Cangiotti & Chim Kei Chan & Wen-Hui Lien, 2022. "ROR2 regulates self-renewal and maintenance of hair follicle stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Dzana Dervovic & Ahmad A. Malik & Edward L. Y. Chen & Masahiro Narimatsu & Nina Adler & Somaieh Afiuni-Zadeh & Dagmar Krenbek & Sebastien Martinez & Ricky Tsai & Jonathan Boucher & Jacob M. Berman & K, 2023. "In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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