Nat Commun:全基因组CRISPR筛选揭示乳腺癌的易感性和mTOR/Hippo协同潜在靶向治疗策略

2021-05-27 xiaozeng MedSci原创

乳腺癌作为影响全球妇女的一大疾病,其发病率和死亡率逐年上升。

乳腺癌作为影响全球妇女的一大疾病,其发病率和死亡率逐年上升。三阴性乳腺癌(TNBC)的定义为缺乏ER(雌激素受体)、PR(孕激素受体)和HER2(人类表皮生长因子受体2)的表达,在年轻患者中发病频繁,约占所有乳腺癌病例的15%。

TNBC与侵袭性病理特征相关,包括组织学评分高、有丝分裂指数高、更高的转移率和复发率、缺乏靶向治疗手段以及患者的预后不良等。TNBC作为一种异质性疾病,尽管已将其进行分类,但由于疾病的异质性,TNBC的发病机制的了解仍有限,这也使得有效治疗策略的开发成为了一项艰巨的挑战。

使用基因组编辑系统(如CRISPR/Cas9技术)进行全基因组范围的遗传筛选已成为系统表征癌症易感性的先进工具。尽管最近的一些研究揭示了体内全基因组CRISPR筛查在非小细胞肺癌和白血病中的作用,但其有效性仍有待进一步的研究。


在该研究中,研究人员采用了无偏倚的体内全基因组CRISPR敲除筛选的方式,以在全基因组水平分析TNBC的癌症易感性,并确定致癌和抑癌通路之间的相互作用。

TNBC的全基因组CRISPR敲除筛选

该研究揭示了TNBC患者中mTOR信号通路和Hippo信号通路是调节肿瘤功能的必不可少的组成成分。通过分析药物基质协同模型和患者来源移植瘤模型,研究人员进一步的建立了该治疗相关性,药理学抑制mTORC1/2和癌蛋白YAP能够有效的降低TNBC的肿瘤发生。


分子水平研究显示,虽然维替泊芬(verteporfin)诱导的对YAP抑制作用会导致细胞凋亡的发生,但torin1介导的对mTORC1/2抑制作用却能够促进巨胞饮(macropinocytosis)作用。Torin1诱导的巨胞饮作用能够进一步的促进维替泊芬的摄取,并显著增强其在癌细胞中的促凋亡作用。

mTOR通路的激活促进了TNBC的发生

总而言之,该研究结果揭示了体内全基因组范围内CRISPR筛选在确定临床上相关的和新型的癌症治疗策略方面的强大功能。


原始出处:

Dai, M., Yan, G., Wang, N. et al. In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy. Nat Commun 12, 3055 (24 May 2021).

 

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    2021-11-29 liye789132251
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    2021-08-14 liuli5079
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    2021-05-29 yuandd
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