气候变化领域集成服务门户(CCPortal): CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping

CCPortal

DOI	10.1073/pnas.2115116118
	CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping
	Naert T.; Tulkens D.; Van Nieuwenhuysen T.; Przybyl J.; Demuynck S.; Van de Rijn M.; Al-Jazrawe M.; Alman B.A.; Coucke P.J.; De Leeneer K.; Vanhove C.; Savvides S.N.; Creytens D.; Vleminckx K.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:47
英文摘要	Cancer precision medicine implies identification of tumor-specific vulnerabilities associated with defined oncogenic pathways. Desmoid tumors are soft-tissue neoplasms strictly driven byWnt signaling network hyperactivation. Despite this clearly defined genetic etiology and the strict and unique implication of the Wnt/β-catenin pathway, no specific molecular targets for these tumors have been identified. To address this caveat, we developed fast, efficient, and penetrant genetic Xenopus tropicalis desmoid tumor models to identify and characterize drug targets. We used multiplexed CRISPR/Cas9 genome editing in these models to simultaneously target a tumor suppressor gene (apc) and candidate dependency genes. Our methodology CRISPR/Cas9 selection-mediated identification of dependencies (CRISPR-SID) uses calculated deviations between experimentally observed gene editing outcomes and deep-learning-predicted double-strand break repair patterns to identify genes under negative selection during tumorigenesis. This revealed EZH2 and SUZ12, both encoding polycomb repressive complex 2 components, and the transcription factor CREB3L1 as genetic dependencies for desmoid tumors. In vivo EZH2 inhibition by Tazemetostat induced partial regression of established autochthonous tumors. In vitro models of patient desmoid tumor cells revealed a direct effect of Tazemetostat on Wnt pathway activity. CRISPR-SID represents a potent approach for in vivo mapping of tumor vulnerabilities and drug target identification. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	APC; Cancer dependency; Desmoid tumor; EZH2; Xenopus
语种	英语
scopus关键词	polycomb repressive complex 2; tazemetostat; transcription factor; transcription factor CREB3L1; transcription factor EZH2; unclassified drug; beta catenin; CREB3L1 protein, human; CTNNB1 protein, human; cyclic AMP responsive element binding protein; EZH2 protein, human; nerve protein; polycomb repressive complex 2; SUZ12 protein, human; transcription factor; transcription factor EZH2; tumor protein; amplicon; animal cell; animal experiment; animal model; animal tissue; Article; carcinogenesis; controlled study; CRISPR-CAS9 system; deep learning; desmoid tumor; double strand break repair; frameshift mutation; gene editing; gene inactivation; genetic selection; human; in vivo study; nonhuman; protein targeting; quantitative analysis; transcription regulation; tumor suppressor gene; Wnt signaling; Xenopus tropicalis; abdominal tumor; animal; clustered regularly interspaced short palindromic repeat; colon polyposis; CRISPR Cas system; fibromatosis; gene expression regulation; genetics; isolation and purification; metabolism; oncogene; procedures; tumor cell line; Xenopus; Abdominal Neoplasms; Adenomatous Polyposis Coli; Animals; beta Catenin; Carcinogenesis; Cell Line, Tumor; Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR-Cas Systems; Cyclic AMP Response Element-Binding Protein; Enhancer of Zeste Homolog 2 Protein; Fibromatosis, Aggressive; Gene Editing; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Nerve Tissue Proteins; Oncogenes; Polycomb Repressive Complex 2; Transcription Factors; Wnt Signaling Pathway; Xenopus
来源期刊	Proceedings of the National Academy of Sciences of the United States of America (IF:9.58[JCR-2018],10.6[5-Year])
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250979
作者单位	Department of Biomedical Molecular Biology, Ghent University, Ghent, 9052, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, 9000, Belgium; Department of Pathology, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Cell Biology, Duke University, School of Medicine, Durham, NC 12422, United States; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium; Department of Electronics and Information Systems, Ghent University, Ghent, 9000, Belgium; VIB Center for Inflammation Research, VIB, Ghent, 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent, 9052, Belgium; Department of Pathology, Ghent University and Ghent University Hospital, Ghent, 9000, Belgium
推荐引用方式 GB/T 7714	Naert T.,Tulkens D.,Van Nieuwenhuysen T.,et al. CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping[J],2021,118(47).
APA	Naert T..,Tulkens D..,Van Nieuwenhuysen T..,Przybyl J..,Demuynck S..,...&Vleminckx K..(2021).CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping.Proceedings of the National Academy of Sciences of the United States of America,118(47).
MLA	Naert T.,et al."CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping".Proceedings of the National Academy of Sciences of the United States of America 118.47(2021).