KIFC1作为肺癌中心体放大相关潜在脆弱性的识别

Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification

CANCER GENE THERAPY

影响因子:5

分区:医学3区 / 生物工程与应用微生物3区遗传学3区医学：研究与实验3区肿瘤学4区

发表日期:2024 Oct

作者: Christopher Zhang, Benson Z Wu, Caterina Di Ciano-Oliveira, Yin Fang Wu, Sharon S Khavkine Binstock, Isabel Soria-Bretones, Nhu-An Pham, Andrew J Elia, Raj Chari, Wan L Lam, Mark R Bray, Tak W Mak, Ming-Sound Tsao, David W Cescon, Kelsie L Thu

DOI: 10.1038/s41417-024-00824-1

摘要

中心体放大（CA）指细胞中中心体数量异常增加，是肺癌及其他恶性肿瘤中的常见现象。虽然CA通过诱导基因组不稳定性（GIN）促进肿瘤发展和进程，但它也引发有害的有丝分裂应激，危及细胞完整性。CA导致多极有丝分裂纺锤体形成，可能引起致命的染色体分离错误。为了维持CA的益处并减轻其后果，恶性细胞依赖适应性机制，这些机制也成为潜在的治疗脆弱点。我们旨在发现与肺癌CA相关的遗传依赖因子。结合CRISPR/Cas9功能基因组学筛查与肿瘤基因组分析，我们鉴定出运动蛋白KIFC1（亦称HSET）为特异性在具有CA的肺腺癌（LUAD）中的潜在脆弱点。KIFC1的表达与LUAD中的CA呈正相关，并与患者预后不良、吸烟史及GIN指标相关。KIFC1基因敲除增强了高基线KIFC1表达的LUAD细胞对CA的敏感性，表现为其聚集多余中心体为伪双极有丝分裂纺锤体的能力减弱。我们的工作提示，抑制KIFC1可通过迫使细胞以多极纺锤体分裂，增强GIN，达到致死水平，为其潜在的治疗应用提供理论基础。

Abstract

Centrosome amplification (CA), an abnormal increase in the number of centrosomes in the cell, is a recurrent phenomenon in lung and other malignancies. Although CA promotes tumor development and progression by inducing genomic instability (GIN), it also induces mitotic stress that jeopardizes cellular integrity. CA leads to the formation of multipolar mitotic spindles that can cause lethal chromosome segregation errors. To sustain the benefits of CA by mitigating its consequences, malignant cells are dependent on adaptive mechanisms that represent therapeutic vulnerabilities. We aimed to discover genetic dependencies associated with CA in lung cancer. Combining a CRISPR/Cas9 functional genomics screen with tumor genomic analyses, we identified the motor protein KIFC1, also known as HSET, as a putative vulnerability specifically in lung adenocarcinoma (LUAD) with CA. KIFC1 expression was positively correlated with CA in LUAD and associated with worse patient outcomes, smoking history, and indicators of GIN. KIFC1 loss-of-function sensitized LUAD cells with high basal KIFC1 expression to potentiation of CA, which was associated with a diminished ability to cluster extra centrosomes into pseudo-bipolar mitotic spindles. Our work suggests that KIFC1 inhibition represents a novel approach for potentiating GIN to lethal levels in LUAD with CA by forcing cells to divide with multipolar spindles, rationalizing further studies to investigate its therapeutic potential.