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Cancer Discov. 2014 Oct;4(10):1168-81. doi: 10.1158/2159-8290.CD-13-0747. Epub 2014 Jul 11.

A large-scale RNAi-based mouse tumorigenesis screen identifies new lung cancer tumor suppressors that repress FGFR signaling.

Author information

1
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
2
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
3
Programs in Gene Function and Expression, Molecular Medicine and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
4
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.
5
Department of Thoracic Medicine, The Prince Charles Hospital and University of Queensland Thoracic Research Centre, Brisbane, Queensland, Australia.
6
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. michael.green@umassmed.edu.

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.

SIGNIFICANCE:

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.

PMID:
25015643
PMCID:
PMC4184919
DOI:
10.1158/2159-8290.CD-13-0747
[Indexed for MEDLINE]
Free PMC Article

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