CRISPR-mediated MECOM depletion retards tumor growth by reducing cancer stem cell properties in lung squamous cell carcinoma.
CRISPR-mediated MECOM depletion retards tumor growth by reducing cancer stem cell properties in lung squamous cell carcinoma.
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CRISPR介导的MECOM耗竭通过降低肺鳞状细胞癌中的癌症干细胞特性来延缓肿瘤生长
DOI：
10.1016/j.ymthe.2022.06.011
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发表时间：
2022-11-02
影响因子：
12.4
通讯作者：
Wu, Nan
中科院分区：
文献类型：
--
作者：
Ma, Yuanyuan;Kang, Bin;Li, Shaolei;Xie, Guoyun;Bi, Jiwang;Li, Fuqiang;An, Guo;Liu, Bing;Li, Jing;Shen, Yue;Xu, Xun;Yang, Huanming;Yang, Yue;Gu, Ying;Wu, Nan
由于缺乏强有力的靶点，靶向治疗肺鳞状细胞癌（LUSC）仍然是一个挑战。在这里，我们通过使用聚集规则间隔短回文重复（CRISPR）介导的方法筛选38个在三对原发肿瘤和患者来源的异种移植（pdx）中普遍扩增的基因，确定MECOM作为LUSC的候选治疗靶点。MECOM高表达与预后差相关。MECOM在LUSC细胞系中的强制表达促进了癌症干细胞（CSC）的特性，而敲除MECOM则抑制了CSC的表型。此外，使用腺病毒系统递送crispr介导的MECOM衰竭盒，该接头由与柯萨奇病毒和腺病毒受体融合的上皮细胞粘附分子（EpCAM）的单链片段变量（scFv）组成，以及由连接到腺病毒六体对称的scFv组成的保护器组成，可以特异性靶向皮下和原位LUSC并延迟肿瘤生长。本研究可为LUSC的治疗提供一种高效、特异的新策略。Ma等人发现MECOM在肺鳞状细胞癌（LUSC）中频繁扩增，促进了癌症干细胞的特性。有趣的是，crispr药物治疗的MECOM耗尽通过系统递送带有工程适配器和保护蛋白的腺病毒载体具有抗肿瘤作用，这表明一种高效率和特异性的新型治疗策略。
Targeted therapy for lung squamous cell carcinoma (LUSC) remains a challenge due to the lack of robust targets. Here, we identified MECOM as a candidate of therapeutic target for LUSC by screening 38 genes that were commonly amplified in three pairs of primary tumors and patient-derived xenografts (PDXs) using a clustered regularly interspaced short palindromic repeats (CRISPR)-mediated approach. High MECOM expression levels were associated with poor prognosis. Forced expression of MECOM in LUSC cell lines promoted cancer stem cell (CSC) properties, and its knockout inhibited CSC phenotypes. Furthermore, systemic delivery of CRISPR-mediated MECOM depletion cassette using adenovirus with an adaptor, which is composed of a single-chain fragment variable (scFv) against epithelial cell adhesion molecules (EpCAM) fused to the ectodomain of coxsackievirus and adenovirus receptor, and a protector, which consists of the scFv connected to the hexon symmetry of the adenovirus, could specifically target subcutaneous and orthotopic LUSC and retard tumor growth. This study could provide a novel therapeutic strategy for LUSC with high efficacy and specificity. Ma et al. identified that MECOM frequently amplified in lung squamous cell carcinoma (LUSC) promoted cancer stem cell properties. Interestingly, CRISPR-medicated MECOM depletion had the antitumor effect using systemic delivery of adenovirus vector with the engineered adaptor and protector proteins, indicating a novel therapeutic strategy with high efficacy and specificity.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
DOI：
10.1158/1078-0432.ccr-14-3039
发表时间：
2015-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gandara DR;Hammerman PS;Sos ML;Lara PN Jr;Hirsch FR
通讯作者：
Hirsch FR
影响因子：
4.6
作者：
Deng, Xiyun;Cao, Yanna;Liu, Yan;Li, Fazhi;Sambandam, Kamalanathan;Rajaraman, Srinivasan;Perkins, Archibald S.;Fields, Alan P.;Hellmich, Mark R.;Townsend, Courtney M., Jr.;Thompson, E. Aubrey;Ko, Tien C.
通讯作者：
Ko, Tien C.
影响因子：
5.6
作者：
Chan, Lai-Sheung;Lung, Hong-Lok;Mak, Nai-Ki
通讯作者：
Mak, Nai-Ki
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F