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

doi:10.1038/nature12464

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

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111 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 language	English (US)
Pages (from-to)	185-190
Number of pages	6
Journal	Nature
Volume	501
Issue number	7466
DOIs	https://doi.org/10.1038/nature12464
State	Published - 2013
Externally published	Yes

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@article{d8109168aa0045bdaecc6cd92244b971,

title = "RNAi screens in mice identify physiological regulators of oncogenic growth",

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.",

author = "Slobodan Beronja and Peter Janki and Evan Heller and Lien, {Wen Hui} and Keyes, {Brice E.} and Naoki Oshimori and Elaine Fuchs",

note = "Funding Information: Acknowledgements We thank J. Fagin for inducible oncogenic Hras mice; S. Williams, M. Schober, A. Rodriguez Folgueras, S. Dewell and D. Schramek for intellectual input; D. Oristian and N. Stokes as mouse specialists; Comparative Bioscience Center (AAALAC accredited) for care of mice in accordance with National Institutes of Health (NIH) guidelines; Genomics Resource Center (C. Zhao, Director) for sequencing; Bioimaging Center (A. North, Director) for advice; Flow Cytometry facility (S. Mazel, Director) for FACS sorting. E.F. is an Investigator of the Howard Hughes Medical Institute.Thisresearchwas supportedbygrantsfromthe NIH (R37-AR27883(E.F.)and K99-AR061469 (S.B.)), Emerald Foundation (E.F.) and Human Frontiers Science Program Postdoctoral Fellowship (S.B.). Copyright: Copyright 2014 Elsevier B.V., All rights reserved.",

year = "2013",

doi = "10.1038/nature12464",

language = "English (US)",

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pages = "185--190",

journal = "Nature",

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T1 - RNAi screens in mice identify physiological regulators of oncogenic growth

AU - Beronja, Slobodan

AU - Janki, Peter

AU - Heller, Evan

AU - Lien, Wen Hui

AU - Keyes, Brice E.

AU - Oshimori, Naoki

AU - Fuchs, Elaine

N1 - Funding Information: Acknowledgements We thank J. Fagin for inducible oncogenic Hras mice; S. Williams, M. Schober, A. Rodriguez Folgueras, S. Dewell and D. Schramek for intellectual input; D. Oristian and N. Stokes as mouse specialists; Comparative Bioscience Center (AAALAC accredited) for care of mice in accordance with National Institutes of Health (NIH) guidelines; Genomics Resource Center (C. Zhao, Director) for sequencing; Bioimaging Center (A. North, Director) for advice; Flow Cytometry facility (S. Mazel, Director) for FACS sorting. E.F. is an Investigator of the Howard Hughes Medical Institute.Thisresearchwas supportedbygrantsfromthe NIH (R37-AR27883(E.F.)and K99-AR061469 (S.B.)), Emerald Foundation (E.F.) and Human Frontiers Science Program Postdoctoral Fellowship (S.B.). Copyright: Copyright 2014 Elsevier B.V., All rights reserved.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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RNAi screens in mice identify physiological regulators of oncogenic growth

Abstract

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