A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors that Repress FGFR Signaling
Program in Gene Function and Expression; Program in Molecular Medicine
Bioinformatics | Cancer Biology | Computational Biology | Genetics and Genomics | Genomics | Integrative Biology
To discover new tumor suppressor genes (TSGs), we developed a functional genomics approach in which immortalized but non-tumorigenic cells were stably transduced with large-scale short hairpin RNA (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 down-regulated in human lung squamous cell carcinomas (hLSCCs). 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.
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Citation: Lin L, Chamberlain L, Pak ML, Nagarajan A, Gupta R, Zhu LJ, Wright CM, Fong KM, Wajapeyee N, Green MR. A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors that Repress FGFR Signaling. Cancer Discov. 2014 Jul 11. [Epub ahead of print] Link to article on publisher's site