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.
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