将KIFC1识别为具有中心体扩增的肺癌中的推定脆弱性
Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification
影响因子:5.00000
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
摘要
中心体扩增（CA）是细胞中的中心体数量的异常增加，是肺部和其他恶性肿瘤中的复发现象。尽管CA通过诱导基因组不稳定性（GIN）促进肿瘤的发展和进展，但它也会诱导有丝分裂应激，从而危及细胞完整性。 CA导致形成多极有丝分裂的纺锤体，可能导致致命的染色体隔离误差。为了通过缓解其后果来维持CA的好处，恶性细胞取决于代表治疗脆弱性的适应性机制。我们旨在发现与肺癌中CA相关的遗传依赖性。将CRISPR/CAS9功能基因组学筛选与肿瘤基因组分析相结合，我们确定了运动蛋白KIFC1，也称为HSET，是一种推定的脆弱性，专门在肺腺癌（LUAD）中。 KIFC1表达与LUAD中的CA呈正相关，并与较差的患者结局，吸烟史和杜松子酒的指标相关。 KIFC1功能丧失敏化的LUAD细胞具有高基础KIFC1表达对CA的增强，这与将额外的centrosomes聚集到伪双极有丝分裂纺锤体中的能力降低有关。我们的工作表明，KIFC1抑制作用代表了一种通过迫使细胞与多极纺锤体分裂的新型方法，将杜松子杜松子升至LUAD的致命水平，从而使进一步的研究合理化以研究其治疗潜力。
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.