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 | |
| State | Published - 2013 |
| Externally published | Yes |
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Cite this
RNAi screens in mice identify physiological regulators of oncogenic growth. / Beronja, Slobodan; Janki, Peter; Heller, Evan; Lien, Wen Hui; Keyes, Brice E.; Oshimori, Naoki; Fuchs, Elaine.
In: Nature, Vol. 501, No. 7466, 2013, p. 185-190.Research output: Contribution to journal › Article
}
TY - JOUR
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
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.
UR - http://www.scopus.com/inward/record.url?scp=84884129997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884129997&partnerID=8YFLogxK
U2 - 10.1038/nature12464
DO - 10.1038/nature12464
M3 - Article
C2 - 23945586
AN - SCOPUS:84884129997
VL - 501
SP - 185
EP - 190
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7466
ER -