Integrative analysis of cancer dependency data and comprehensive phosphoproteomics data revealed the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant colorectal cancer†

IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular omics Pub Date : 2023-05-17 DOI:10.1039/D3MO00042G
Daigo Gunji, Ryohei Narumi, Satoshi Muraoka, Junko Isoyama, Narumi Ikemoto, Mimiko Ishida, Takeshi Tomonaga, Yoshiharu Sakai, Kazutaka Obama and Jun Adachi
{"title":"Integrative analysis of cancer dependency data and comprehensive phosphoproteomics data revealed the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant colorectal cancer†","authors":"Daigo Gunji, Ryohei Narumi, Satoshi Muraoka, Junko Isoyama, Narumi Ikemoto, Mimiko Ishida, Takeshi Tomonaga, Yoshiharu Sakai, Kazutaka Obama and Jun Adachi","doi":"10.1039/D3MO00042G","DOIUrl":null,"url":null,"abstract":"<p >Colorectal cancer (CRC), a common malignant tumour of the gastrointestinal tract, is a life-threatening cancer worldwide. Mutations in KRAS and BRAF, the major driver mutation subtypes in CRC, activate the RAS pathway, contribute to tumorigenesis in CRC and are being investigated as potential therapeutic targets. Despite recent advances in clinical trials targeting KRASG12C or RAS downstream signalling molecules for KRAS-mutant CRC, there is a lack of effective therapeutic interventions. Therefore, understanding the unique molecular characteristics of KRAS-mutant CRC is essential for identifying molecular targets and developing novel therapeutic interventions. We obtained in-depth proteomics and phosphoproteomics quantitative data for over 7900 proteins and 38 700 phosphorylation sites in cells from 35 CRC cell lines and performed informatic analyses, including proteomics-based coexpression analysis and correlation analysis between phosphoproteomics data and cancer dependency scores of the corresponding phosphoproteins. Our results revealed novel dysregulated protein–protein associations enriched specifically in KRAS-mutant cells. Our phosphoproteomics analysis revealed activation of EPHA2 kinase and downstream tight junction signalling in KRAS-mutant cells. Furthermore, the results implicate the phosphorylation site Y378 in the tight junction protein PARD3 as a cancer vulnerability in KRAS-mutant cells. Together, our large-scale phosphoproteomics and proteomics data across 35 steady-state CRC cell lines represent a valuable resource for understanding the molecular characteristics of oncogenic mutations. Our approach to predicting cancer dependency from phosphoproteomics data identified the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant CRC.</p>","PeriodicalId":19065,"journal":{"name":"Molecular omics","volume":" 8","pages":" 624-639"},"PeriodicalIF":3.0000,"publicationDate":"2023-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular omics","FirstCategoryId":"99","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2023/mo/d3mo00042g","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Colorectal cancer (CRC), a common malignant tumour of the gastrointestinal tract, is a life-threatening cancer worldwide. Mutations in KRAS and BRAF, the major driver mutation subtypes in CRC, activate the RAS pathway, contribute to tumorigenesis in CRC and are being investigated as potential therapeutic targets. Despite recent advances in clinical trials targeting KRASG12C or RAS downstream signalling molecules for KRAS-mutant CRC, there is a lack of effective therapeutic interventions. Therefore, understanding the unique molecular characteristics of KRAS-mutant CRC is essential for identifying molecular targets and developing novel therapeutic interventions. We obtained in-depth proteomics and phosphoproteomics quantitative data for over 7900 proteins and 38 700 phosphorylation sites in cells from 35 CRC cell lines and performed informatic analyses, including proteomics-based coexpression analysis and correlation analysis between phosphoproteomics data and cancer dependency scores of the corresponding phosphoproteins. Our results revealed novel dysregulated protein–protein associations enriched specifically in KRAS-mutant cells. Our phosphoproteomics analysis revealed activation of EPHA2 kinase and downstream tight junction signalling in KRAS-mutant cells. Furthermore, the results implicate the phosphorylation site Y378 in the tight junction protein PARD3 as a cancer vulnerability in KRAS-mutant cells. Together, our large-scale phosphoproteomics and proteomics data across 35 steady-state CRC cell lines represent a valuable resource for understanding the molecular characteristics of oncogenic mutations. Our approach to predicting cancer dependency from phosphoproteomics data identified the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant CRC.

Abstract Image

癌症依赖性数据和综合磷酸蛋白质组学数据的综合分析显示,EPHA2-PARD3轴是KRAS-突变型癌症的癌症脆弱性。
癌症(CRC)是一种常见的胃肠道恶性肿瘤,是世界范围内危及生命的癌症。KRAS和BRAF是CRC的主要驱动突变亚型,它们的突变激活RAS途径,有助于CRC的肿瘤发生,并作为潜在的治疗靶点进行研究。尽管针对KRAS突变型CRC的KRASG12C或RAS下游信号分子的临床试验最近取得了进展,但缺乏有效的治疗干预措施。因此,了解KRAS突变体CRC的独特分子特征对于确定分子靶点和开发新的治疗干预措施至关重要。我们获得了7900多种蛋白质和38种蛋白质的深入蛋白质组学和磷酸蛋白质组学定量数据 来自35个CRC细胞系的细胞中的700个磷酸化位点,并进行了信息学分析,包括基于蛋白质组学的共表达分析和磷酸蛋白质组学数据与相应磷酸蛋白的癌症依赖性得分之间的相关性分析。我们的研究结果揭示了KRAS突变细胞中特异性富集的新的失调蛋白-蛋白关联。我们的磷酸蛋白质组学分析揭示了KRAS突变细胞中EPHA2激酶的激活和下游紧密连接信号传导。此外,该结果表明紧密连接蛋白PARD3中的磷酸化位点Y378是KRAS-突变细胞中的癌症易感性。总之,我们在35个稳态CRC细胞系中的大规模磷酸蛋白质组学和蛋白质组学数据为理解致癌突变的分子特征提供了宝贵的资源。我们通过磷酸蛋白质组学数据预测癌症依赖性的方法确定EPHA2-PARD3轴是KRAS-突变CRC中的癌症脆弱性。
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
Molecular omics
Molecular omics Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
5.40
自引率
3.40%
发文量
91
期刊介绍: Molecular Omics publishes high-quality research from across the -omics sciences. Topics include, but are not limited to: -omics studies to gain mechanistic insight into biological processes – for example, determining the mode of action of a drug or the basis of a particular phenotype, such as drought tolerance -omics studies for clinical applications with validation, such as finding biomarkers for diagnostics or potential new drug targets -omics studies looking at the sub-cellular make-up of cells – for example, the subcellular localisation of certain proteins or post-translational modifications or new imaging techniques -studies presenting new methods and tools to support omics studies, including new spectroscopic/chromatographic techniques, chip-based/array technologies and new classification/data analysis techniques. New methods should be proven and demonstrate an advance in the field. Molecular Omics only accepts articles of high importance and interest that provide significant new insight into important chemical or biological problems. This could be fundamental research that significantly increases understanding or research that demonstrates clear functional benefits. Papers reporting new results that could be routinely predicted, do not show a significant improvement over known research, or are of interest only to the specialist in the area are not suitable for publication in Molecular Omics.
×
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