Abstract
Genetic aberrations driving pro-oncogenic and pro-metastatic activity remain an elusive target in the quest of precision oncology. To identify such drivers, we use an animal model of KRAS-mutant lung adenocarcinoma to perform an in vivo functional screen of 217 genetic aberrations selected from lung cancer genomics datasets. We identify 28 genes whose expression promoted tumor metastasis to the lung in mice. We employ two tools for examining the KRAS-dependence of genes identified from our screen: 1) a human lung cell model containing a regulatable mutant KRAS allele and 2) a lentiviral system permitting co-expression of DNA-barcoded cDNAs with Cre recombinase to activate a mutant KRAS allele in the lungs of mice. Mechanistic evaluation of one gene, GATAD2B, illuminates its role as a dual activity gene, promoting both pro-tumorigenic and pro-metastatic activities in KRAS-mutant lung cancer through interaction with c-MYC and hyperactivation of the c-MYC pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma of Lung / genetics*
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Adenocarcinoma of Lung / mortality
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Adenocarcinoma of Lung / pathology
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Adenocarcinoma of Lung / therapy
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Animals
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Cell Line, Tumor
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Female
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GATA Transcription Factors / antagonists & inhibitors
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GATA Transcription Factors / genetics*
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GATA Transcription Factors / metabolism
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Gene Expression Regulation, Neoplastic*
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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High-Throughput Screening Assays
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Humans
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Integrases / genetics
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Integrases / metabolism
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Lentivirus / genetics
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Lentivirus / metabolism
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Lung Neoplasms / genetics*
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Lung Neoplasms / therapy
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Mice
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Mice, Nude
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Neoplasm Metastasis
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics*
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Proto-Oncogene Proteins p21(ras) / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Repressor Proteins
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Signal Transduction
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Survival Analysis
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Xenograft Model Antitumor Assays
Substances
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GATA Transcription Factors
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GATAD2B protein, human
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KRAS protein, human
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MYC protein, human
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Repressor Proteins
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Cre recombinase
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Integrases
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Proto-Oncogene Proteins p21(ras)