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Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous KrasG12D.

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Date
2019-11-20
Authors
Huang, Jianguo
Chen, Mark
Xu, Eric S
Luo, Lixia
Ma, Yan
Huang, Wesley
Floyd, Warren
Klann, Tyler S
Kim, So Young
Gersbach, Charles A
Cardona, Diana M
Kirsch, David G
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(12 total)
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Abstract
Cooperating gene mutations are typically required to transform normal cells enabling growth in soft agar or in immunodeficient mice. For example, mutations in Kras and transformation-related protein 53 (Trp53) are known to transform a variety of mesenchymal and epithelial cells in vitro and in vivo. Identifying other genes that can cooperate with oncogenic Kras and substitute for Trp53 mutation has the potential to lead to new insights into mechanisms of carcinogenesis. Here, we applied a genome-wide CRISPR/Cas9 knockout screen in KrasG12D immortalized mouse embryonic fibroblasts (MEFs) to search for genes that when mutated cooperate with oncogenic Kras to induce transformation. We also tested if mutation of the identified candidate genes could cooperate with KrasG12D to generate primary sarcomas in mice. In addition to identifying the well-known tumor suppressor cyclin dependent kinase inhibitor 2A (Cdkn2a), whose alternative reading frame product p19 activates Trp53, we also identified other putative tumor suppressors, such as F-box/WD repeat-containing protein 7 (Fbxw7) and solute carrier family 9 member 3 (Slc9a3). Remarkably, the TCGA database indicates that both FBXW7 and SLC9A3 are commonly co-mutated with KRAS in human cancers. However, we found that only mutation of Trp53 or Cdkn2a, but not Fbxw7 or Slc9a3 can cooperate with KrasG12D to generate primary sarcomas in mice. These results show that mutations in oncogenic Kras and either Fbxw7 or Slc9a3 are sufficient for transformation in vitro, but not for in vivo sarcomagenesis.
Type
Journal article
Subject
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MOUSE MODEL
CANCER
P53
MUTATIONS
GROWTH
Permalink
https://hdl.handle.net/10161/19753
Published Version (Please cite this version)
10.1038/s41598-019-53572-w
Publication Info
Huang, Jianguo; Chen, Mark; Xu, Eric S; Luo, Lixia; Ma, Yan; Huang, Wesley; ... Kirsch, David G (2019). Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous KrasG12D. Scientific reports, 9(1). pp. 17220. 10.1038/s41598-019-53572-w. Retrieved from https://hdl.handle.net/10161/19753.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Cardona

Diana Marcella Cardona

Associate Professor of Pathology
I am active in translational research involving gastrointestinal/hepatobiliary pathology [specifically transplant related pathology (GVHD and rejection) and carcinogenesis of the pancreas] and bone and soft tissue malignancies [imaging techniques for intraoperative margin assessment].
Gersbach

Charles Gersbach

John W. Strohbehn Distinguished Professor of Biomedical Engineering
Kim

So Young Kim

Associate Research Professor in Molecular Genetics and Microbiology
Kirsch

David Guy Kirsch

Barbara Levine University Distinguished Professor
My clinical interests are the multi-modality care of patients with bone and soft tissue sarcomas and developing new sarcoma therapies. My laboratory interests include utilizing mouse models of cancer to study cancer and radiation biology in order to develop new cancer therapies in the pre-clinical setting.
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