Title
A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors that Repress FGFR Signaling
UMMS Affiliation
Program in Gene Function and Expression; Program in Molecular Medicine
Publication Date
2014-10
Document Type
Article
Disciplines
Bioinformatics | Cancer Biology | Computational Biology | Genetics and Genomics | Genomics | Integrative Biology
Abstract
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.
DOI of Published Version
10.1158/2159-8290.CD-13-0747
Source
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 Oct;4(10):1168-81. doi: 10.1158/2159-8290.CD-13-0747. Epub 2014 Jul 11. PubMed PMID: 25015643; PubMed Central PMCID: PMC4184919. Link to article on publisher's site
Journal/Book/Conference Title
Cancer discovery
Related Resources
PubMed ID
25015643
Repository Citation
Lin, Ling; Chamberlain, Lynn; Pak, Magnolia L.; Nagarajan, Arvindhan; Gupta, Romi; Zhu, Lihua Julie; Wright, Casey M.; Fong, Kwun M.; Wajapeyee, Narendra; and Green, Michael R., "A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors that Repress FGFR Signaling" (2014). Program in Gene Function and Expression Publications and Presentations. 257.
https://escholarship.umassmed.edu/pgfe_pp/257
Comments
First author Ling Lin was a doctoral student in the Interdisciplinary Graduate Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.