Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Stephan Krieg, Thomas Rohde, Tobias Rausch, Luise Butthof, Lena Wendler-Link, Christoph Eckert, Kai Breuhahn, Bruno Galy, Jan Korbel, Maximilian Billmann, Marco Breinig, Darjus F Tschaharganeh
{"title":"Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers.","authors":"Stephan Krieg, Thomas Rohde, Tobias Rausch, Luise Butthof, Lena Wendler-Link, Christoph Eckert, Kai Breuhahn, Bruno Galy, Jan Korbel, Maximilian Billmann, Marco Breinig, Darjus F Tschaharganeh","doi":"10.1186/s13073-024-01357-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions.</p><p><strong>Methods: </strong>We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities.</p><p><strong>Results: </strong>We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential.</p><p><strong>Conclusions: </strong>Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"83"},"PeriodicalIF":10.4000,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11181659/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Medicine","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13073-024-01357-w","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions.

Methods: We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities.

Results: We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential.

Conclusions: Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.

线粒体铁蛋白2是染色体8p缺失癌症的合成致死靶点。
背景:体细胞拷贝数改变是癌症的一个特征,它为治疗提供了独特的机会。在此,我们重点研究了携带 8p 染色体缺失的肿瘤的特殊脆弱性:我们开发并应用了癌症基因组图谱(The Cancer Genome Atlas,TCGA)、癌症依赖性图谱(Cancer Dependency Map,DepMap)和癌症细胞系百科全书(Cancer Cell Line Encyclopedia)的综合分析方法,以确定8p染色体特异性易损性。我们在体外和体内采用了正交基因靶向策略,包括短发夹核糖核酸介导的基因敲除和CRISPR/Cas9介导的基因敲除,以验证漏洞:结果:我们发现SLC25A28(又称MFRN2)是携带8p染色体缺失的肿瘤的特异性易感基因。结果:我们发现SLC25A28(又称MFRN2)是染色体8p缺失肿瘤的特异性易感基因,我们证明MFRN2缺失的易感性是由其旁系亲属SLC25A37(又称MFRN1)的表达决定的,SLC25A37位于染色体8p上。与它们作为线粒体铁转运体的功能相一致,MFRN1/2旁系亲属蛋白缺乏会严重损害线粒体呼吸,诱导铁硫簇蛋白的全面耗竭,并导致DNA损伤和细胞死亡。在临床前小鼠异种移植实验中,缺失 MFRN1 的肿瘤中 MFRN2 的耗竭导致肿瘤生长受阻,甚至肿瘤被根除,凸显了其治疗潜力:我们的数据揭示了MFRN2是染色体8p缺失癌症的治疗靶点,并提名MFNR1为MFRN2导向疗法的辅助生物标记物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信