title: A large-scale RNAi-based mouse tumorigenesis screen identifies new lung cancer tumor suppressors that repress FGFR signaling.
abstract: To discover new tumor-suppressor genes (TSG), we developed a functional genomics approach in which immortalized but nontumorigenic cells were stably transduced with large-scale shRNA pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor samples. Using this approach, we identified 24 TSGs that were significantly downregulated in human lung squamous cell carcinomas (hLSCC). Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs. Remarkably, we found that 17 of the TSGs encode repressors of FGFR signaling. Knockdown of 14 of these TSGs transformed immortalized human bronchial epithelial cells and, in most cases, rendered them sensitive to FGFR inhibitors. Our results indicate that increased FGFR signaling promotes tumorigenesis in many hLSCCs that lack FGFR1 amplification or activating mutations.
  
  
  CONCLUSIONS
  A functional genomics approach identifies new lung TSGs whose loss aberrantly increases FGFR signaling to promote tumorigenesis. These TSGs are frequently downregulated in hLSCCs, indicating that increased FGFR signaling promotes tumorigenesis in many hLSCCs lacking FGFR1 amplification or activating mutations.
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Lynn
authors.initials: L
authors.lastname: Chamberlain
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Magnolia L
authors.initials: ML
authors.lastname: Pak
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Arvindhan
authors.initials: A
authors.lastname: Nagarajan
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Romi
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Programs in Gene Function and Expression, Molecular Medicine and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: University of Queensland, School of Medicine, Brisbane, Queensland, Australia. Department of Thoracic Medicine, The Prince Charles Hospital and University of Queensland Thoracic Research Centre, Brisbane, Queensland, Australia.
authors.forename: Casey M
authors.initials: CM
authors.lastname: Wright
authors.affiliation: Department of Thoracic Medicine, The Prince Charles Hospital and University of Queensland Thoracic Research Centre, Brisbane, Queensland, Australia.
authors.forename: Kwun M
authors.initials: KM
authors.lastname: Fong
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Narendra
authors.initials: N
authors.lastname: Wajapeyee
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. michael.green@umassmed.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; C109073:SH3BP2 protein, human; D025521:Tumor Suppressor Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1