TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling

IF 17.3 1区 生物学 Q1 CELL BIOLOGY
Wei-Ting Lu, Lykourgos-Panagiotis Zalmas, Chris Bailey, James R. M. Black, Carlos Martinez-Ruiz, Oriol Pich, Francisco Gimeno-Valiente, Ieva Usaite, Alastair Magness, Kerstin Thol, Thomas A. Webber, Ming Jiang, Rebecca E. Saunders, Yun-Hsin Liu, Dhruva Biswas, Esther O. Ige, Birgit Aerne, Eva Grönroos, Subramanian Venkatesan, Georgia Stavrou, Takahiro Karasaki, Maise Al Bakir, Matthew Renshaw, Hang Xu, Deborah Schneider-Luftman, Natasha Sharma, Laura Tovini, Mariam Jamal-Hanjani, Sarah E. McClelland, Kevin Litchfield, Nicolai J. Birkbak, Michael Howell, Nicolas Tapon, Kasper Fugger, Nicholas McGranahan, Jiri Bartek, Nnennaya Kanu, Charles Swanton
{"title":"TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling","authors":"Wei-Ting Lu, Lykourgos-Panagiotis Zalmas, Chris Bailey, James R. M. Black, Carlos Martinez-Ruiz, Oriol Pich, Francisco Gimeno-Valiente, Ieva Usaite, Alastair Magness, Kerstin Thol, Thomas A. Webber, Ming Jiang, Rebecca E. Saunders, Yun-Hsin Liu, Dhruva Biswas, Esther O. Ige, Birgit Aerne, Eva Grönroos, Subramanian Venkatesan, Georgia Stavrou, Takahiro Karasaki, Maise Al Bakir, Matthew Renshaw, Hang Xu, Deborah Schneider-Luftman, Natasha Sharma, Laura Tovini, Mariam Jamal-Hanjani, Sarah E. McClelland, Kevin Litchfield, Nicolai J. Birkbak, Michael Howell, Nicolas Tapon, Kasper Fugger, Nicholas McGranahan, Jiri Bartek, Nnennaya Kanu, Charles Swanton","doi":"10.1038/s41556-024-01558-w","DOIUrl":null,"url":null,"abstract":"<p>Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including <i>FAT1</i>, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that <i>FAT1</i> alterations are positively selected before genome doubling and associated with HR deficiency. <i>FAT1</i> ablation causes persistent replication stress, an elevated mitotic failure rate, nuclear deformation and elevated structural CIN, including chromosome translocations and radial chromosomes. <i>FAT1</i> loss contributes to whole-genome doubling (a form of numerical CIN) through the dysregulation of YAP1. Co-depletion of <i>YAP1</i> partially rescues numerical CIN caused by <i>FAT1</i> loss but does not relieve HR deficiencies, nor structural CIN. Importantly, overexpression of constitutively active YAP1<sup>5SA</sup> is sufficient to induce numerical CIN. Taken together, we show that <i>FAT1</i> loss in NSCLC attenuates HR and exacerbates CIN through two distinct downstream mechanisms, leading to increased tumour heterogeneity.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"3 1","pages":""},"PeriodicalIF":17.3000,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41556-024-01558-w","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency. FAT1 ablation causes persistent replication stress, an elevated mitotic failure rate, nuclear deformation and elevated structural CIN, including chromosome translocations and radial chromosomes. FAT1 loss contributes to whole-genome doubling (a form of numerical CIN) through the dysregulation of YAP1. Co-depletion of YAP1 partially rescues numerical CIN caused by FAT1 loss but does not relieve HR deficiencies, nor structural CIN. Importantly, overexpression of constitutively active YAP15SA is sufficient to induce numerical CIN. Taken together, we show that FAT1 loss in NSCLC attenuates HR and exacerbates CIN through two distinct downstream mechanisms, leading to increased tumour heterogeneity.

Abstract Image

求助全文
约1分钟内获得全文 求助全文
来源期刊
Nature Cell Biology
Nature Cell Biology 生物-细胞生物学
CiteScore
28.40
自引率
0.90%
发文量
219
审稿时长
3 months
期刊介绍: Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to: -Autophagy -Cancer biology -Cell adhesion and migration -Cell cycle and growth -Cell death -Chromatin and epigenetics -Cytoskeletal dynamics -Developmental biology -DNA replication and repair -Mechanisms of human disease -Mechanobiology -Membrane traffic and dynamics -Metabolism -Nuclear organization and dynamics -Organelle biology -Proteolysis and quality control -RNA biology -Signal transduction -Stem cell biology
×
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