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 B. Mills, Don L. Gibbons () and Kenneth L. Scott
Additional contact information
Caitlin L. Grzeskowiak: Baylor College of Medicine
Samrat T. Kundu: The University of Texas MD Anderson Cancer Center
Xiulei Mo: Emory University School of Medicine
Andrei A. Ivanov: Emory University School of Medicine
Oksana Zagorodna: Baylor College of Medicine
Hengyu Lu: Baylor College of Medicine
Richard H. Chapple: Baylor College of Medicine
Yiu Huen Tsang: Baylor College of Medicine
Daniela Moreno: Baylor College of Medicine
Maribel Mosqueda: University of Texas MD Anderson Cancer Center
Karina Eterovic: University of Texas MD Anderson Cancer Center
Jared J. Fradette: The University of Texas MD Anderson Cancer Center
Sumreen Ahmad: The University of Texas MD Anderson Cancer Center
Fengju Chen: Baylor College of Medicine
Zechen Chong: The University of Texas MD Anderson Cancer Center
Ken Chen: The University of Texas MD Anderson Cancer Center
Chad J. Creighton: Baylor College of Medicine
Haian Fu: Emory University School of Medicine
Gordon B. Mills: University of Texas MD Anderson Cancer Center
Don L. Gibbons: The University of Texas MD Anderson Cancer Center
Kenneth L. Scott: Baylor College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04572-3

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