RNAi screens in mice identify physiological regulators of oncogenic growth.
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.
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University, New York, New York 10065, USA.
Slobodan
S
Beronja
Peter
P
Janki
Evan
E
Heller
Wen-Hui
WH
Lien
Brice E
BE
Keyes
Naoki
N
Oshimori
Elaine
E
Fuchs
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D016678:Genome / Q000235:genetics; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics*; D034622:RNA Interference; D015203:Reproducibility of Results; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; C486273:Mllt6 protein, mouse; D009363:Neoplasm Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D015689:Oncogene Protein p21(ras)