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; Kenneth L. Scott

doi:10.1038/s41467-018-04572-3

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. GibbonsKenneth L. Scott

Cell Developmental and Cancer Biology

Research output: Contribution to journal › Article › peer-review

31 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 language	English (US)
Article number	2732
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04572-3
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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. B., ... Scott, K. L. (2018). In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer. Nature communications, 9(1), Article 2732. https://doi.org/10.1038/s41467-018-04572-3

Grzeskowiak, CL, Kundu, ST, Mo, X, Ivanov, AA, Zagorodna, O, Lu, H, Chapple, RH, Tsang, YH, Moreno, D, Mosqueda, M, Eterovic, K, Fradette, JJ, Ahmad, S, Chen, F, Chong, Z, Chen, K, Creighton, CJ, Fu, H, Mills, GB, Gibbons, DL & Scott, KL 2018, 'In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer', Nature communications, vol. 9, no. 1, 2732. https://doi.org/10.1038/s41467-018-04572-3

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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.",

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

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AU - Ivanov, Andrei A.

AU - Zagorodna, Oksana

AU - Lu, Hengyu

AU - Chapple, Richard H.

AU - Tsang, Yiu Huen

AU - Moreno, Daniela

AU - Mosqueda, Maribel

AU - Eterovic, Karina

AU - Fradette, Jared J.

AU - Ahmad, Sumreen

AU - Chen, Fengju

AU - Chong, Zechen

AU - Chen, Ken

AU - Creighton, Chad J.

AU - Fu, Haian

AU - Mills, Gordon B.

AU - Gibbons, Don L.

AU - Scott, Kenneth L.

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

Abstract

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