英国弗朗西斯·克里克研究所Charles Swanton等研究人员合作发现，TRACERx分析揭示了FAT1在通过Hippo信号通路，调节染色体不稳定性和全基因组倍增中的作用。相关论文于2024年12月30日在线发表于国际学术期刊《自然—细胞生物学》。

研究人员对TRACERx非小细胞肺癌（NSCLC）队列中，驱动事件的系统性表征发现，包括FAT1在内的六个基因的遗传改变，会导致同源重组（HR）修复缺陷和染色体不稳定性（CIN）。通过正交的遗传和实验方法，研究人员证明FAT1改变在基因组倍增之前被积极选择，并与HR缺陷相关。

FAT1的去除会引起持续的复制应激、升高的有丝分裂失败率、细胞核变形以及升高的结构性CIN，包括染色体易位和放射状染色体。FAT1丧失通过YAP1的失调促进全基因组倍增（一种数值CIN形式）。共去除YAP1部分拯救了FAT1丧失引起的数值CIN，但不能缓解HR缺陷或结构性CIN。重要的是，恒定激活的YAP1^5SA的过表达足以诱导数值CIN。

综合来看，研究人员展示了FAT1在NSCLC中的丧失，通过两种不同的下游机制减弱HR并加剧CIN，从而导致肿瘤异质性增加。

研究人员表示，CIN在实体肿瘤中常见，通过增加肿瘤内异质性，促进演化适应并导致较差的预后。

附：英文原文

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

Author: Lu, Wei-Ting, Zalmas, Lykourgos-Panagiotis, Bailey, Chris, Black, James R. M., Martinez-Ruiz, Carlos, Pich, Oriol, Gimeno-Valiente, Francisco, Usaite, Ieva, Magness, Alastair, Thol, Kerstin, Webber, Thomas A., Jiang, Ming, Saunders, Rebecca E., Liu, Yun-Hsin, Biswas, Dhruva, Ige, Esther O., Aerne, Birgit, Grnroos, Eva, Venkatesan, Subramanian, Stavrou, Georgia, Karasaki, Takahiro, Al Bakir, Maise, Renshaw, Matthew, Xu, Hang, Schneider-Luftman, Deborah, Sharma, Natasha, Tovini, Laura, Jamal-Hanjani, Mariam, McClelland, Sarah E., Litchfield, Kevin, Birkbak, Nicolai J., Howell, Michael, Tapon, Nicolas, Fugger, Kasper, McGranahan, Nicholas, Bartek, Jiri, Kanu, Nnennaya, Swanton, Charles

Issue&Volume: 2024-12-30

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.

DOI: 10.1038/s41556-024-01558-w

Source: https://www.nature.com/articles/s41556-024-01558-w