American Association for Cancer Research
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Supplementary Methods, Figures S1 - S14, Tables S1, S3 - S10 from A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors That Repress FGFR Signaling

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posted on 2023-04-03, 20:42 authored by Ling Lin, Lynn Chamberlain, Magnolia L. Pak, Arvindhan Nagarajan, Romi Gupta, Lihua J. Zhu, Casey M. Wright, Kwun M. Fong, Narendra Wajapeyee, Michael R. Green

Supplementary Information includes: Supplementary Methods providing additional information on experimental techniques and data analysis; Supplementary Figures S1-S14 providing critical control experiments and raw data analyses for experiments presented in the main manuscript; and Supplementary Tables S1-S10 summarizing data presented in the main manuscript as well as listing reagents.

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ARTICLE 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. Cancer Discov; 4(10); 1168–81. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 1103