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

• Type of Material: Article
• Authors: Caitlin L. Grzeskowiak, Baylor College of Medicine; Samrat T. Kundu, University of Texas; Xiulei Mo, Emory University; Andrey Andreyevich Ivanov, Emory University; 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; Karina Eterovic, University of Texas; Jared J. Fradette, University of Texas; Sumreen Ahmad, University of Texas; Femgju Chen, Baylor College of Medicine; Zechen Chong, University of Texas; Ken Chen, University of Texas; Chad J. Creighton, Baylor College of Medicine; Haian Fu, Emory University; Gordan B. Mills, University of Texas; Don L. Gibbons, University of Texas; Kenneth L. Scott, Baylor College of Medicine
• Language: English
• Date: 2018-07-16
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2018
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-04572-3
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 2732
• End Page: 2732
• Grant/Funding Information: This project was also supported by the Cancer Target Discovery and Development Network grants U01CA168449 and U01CA217875 to H.F.; This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH/NCI grant (P30CA125123) and Cytometry and Cell Sorting Core Facility with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574).; This project was also supported by the Cancer Prevention and Research Institute of Texas (CPRIT; RP140216) by funding to K.L.S., the Department of Defense (LC110216) by funding to K..L.S. and D.LG., an MD Anderson Cancer Center Physician Scientist Award to D.L.G., and by the NIH (U01CA168394) by funding to K..L.S. and G.B.M. H. L. was supported by the CPRIT Pre-Doctoral Fellowship (RP140102).
• Keywords: ANAPLASTIC LYMPHOMA KINASE; Science & Technology - Other Topics; Science & Technology; PANCREATIC-CANCER; CHROMATIN REMODELING COMPLEX; K-RAS; GROWTH-FACTOR; Multidisciplinary Sciences; MOUSE MODEL; GENE-EXPRESSION SIGNATURE; PROTEIN-PROTEIN INTERACTIONS; C-MYC; MI-2/NURD COMPLEX
• Research Categories: Health Sciences, Oncology; Biology, Molecular

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.