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

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 YAP1<sup>5SA</sup> 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.

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Journal
Nature Cell Biology
Published
2024-12-30
DOI
https://doi.org/10.1038/s41556-024-01558-w
Citations
7
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
2.28

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article

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

Kevin Litchfield, Wei-Ting Lu, N. Sharma, Charles Swanton et al.
7 citations
Nature Cell Biology
Hippo pathway signaling and YAP/TAZ
2.28
article

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

Kevin Litchfield, Wei-Ting Lu, N. Sharma, Charles Swanton, Takahiro Karasaki, T.D. Webber, Birgit L. Aerne, James R. Black, Oriol Pich, Kasper Fugger, Maise Al Bakir, Subramanian Venkatesan, Laura Tovini, Lykourgos‐Panagiotis Zalmas, Alastair Magness, Sarah E. McClelland, Georgia Stavrou, Dhruva Biswas, Mariam Jamal‐Hanjani, Eva Grönroos, Deborah Schneider-Luftman, Ieva Usaite, Kerstin Thol, Nicholas McGranahan, Matthew J. Renshaw, Nnennaya Kanu, Carlos Martínez‐Ruiz, Michael Howell, Francisco Gimeno-Valiente, Chris Bailey, Nicolas Tapon, Nicolai J. Birkbak, Jiří Bártek, Yun-Hsin Liu, Hang Xu, Rebecca E. Saunders, Ming Jiang, Esther O. Ige
article en
7 citations

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 YAP1<sup>5SA</sup> 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.

Nature Cell BiologyVol. 27(1)
Queen Mary University of London (GB), Aarhus University (DK), Science for Life Laboratory (SE), The Francis Crick Institute (GB), Cancer Research UK (GB), Aarhus University Hospital (DK), Karolinska Institutet (SE), London Cancer (GB), CRUK Lung Cancer Centre of Excellence (GB), Danish Cancer Society (DK), Toranomon Hospital (JP), University College London (GB)
Breast Cancer Research Foundation, Melanoma Research Alliance, Memorial Sloan-Kettering Cancer Center, Aarhus Universitet, Wellcome Trust, Francis Crick Institute, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, University College London, European Commission, Rosetrees Trust, Aarhus Universitets Forskningsfond, Lundbeckfonden, Novo Nordisk, Novo Nordisk Fonden, H. Lundbeck A/S, CRUK Lung Cancer Centre of Excellence, Medical Research Council
Openalex Percentile: Top 12%
Hippo pathway signaling and YAP/TAZ
2.28
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