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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • DNA Methylation
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Heterografts
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism*
  • Mice
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference*
  • RNA, Small Interfering / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Signal Transduction*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • RNA, Small Interfering
  • SH3BP2 protein, human
  • Tumor Suppressor Proteins
  • Receptor, Fibroblast Growth Factor, Type 1