In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer

Caitlin L. Grzeskowiak, Samrat T. Kundu, Xiulei Mo, Andrei A. Ivanov, Oksana Zagorodna, Hengyu Lu, Richard H. Chapple, Yiu Huen Tsang, Daniela Moreno, Maribel Mosqueda, Karina Eterovic, Jared J. Fradette, Sumreen Ahmad, Fengju Chen, Zechen Chong, Ken Chen, Chad J. Creighton, Haian Fu, Gordon Mills, Don L. GibbonsKenneth L. Scott

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Article number2732
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Grzeskowiak, C. L., Kundu, S. T., Mo, X., Ivanov, A. A., Zagorodna, O., Lu, H., Chapple, R. H., Tsang, Y. H., Moreno, D., Mosqueda, M., Eterovic, K., Fradette, J. J., Ahmad, S., Chen, F., Chong, Z., Chen, K., Creighton, C. J., Fu, H., Mills, G., ... Scott, K. L. (2018). In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer. Nature Communications, 9(1), [2732]. https://doi.org/10.1038/s41467-018-04572-3