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.
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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. This research was supported by grants from the NIH (R37-AR27883 (E.F.) and K99-AR061469 (S.B.)), Emerald Foundation (E.F.) and Human Frontiers Science Program Postdoctoral Fellowship (S.B.).
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-20. (PDF 27465 kb)
This file contains Supplementary Tables 1-5. The page numbers for each of the tables are as follows: 1) 1-71, 2) 72-180, 3) 181-188, 4) 189-200 and 5) 201. (PDF 6474 kb)
This file contains searchable lists of genes presented in Supplementary Tables 1-4. (XLSX 554 kb)
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Beronja, S., Janki, P., Heller, E. et al. RNAi screens in mice identify physiological regulators of oncogenic growth. Nature 501, 185–190 (2013). https://doi.org/10.1038/nature12464
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