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全基因组 RNAi 筛选揭示了乳腺癌干细胞的关键治疗靶点。

A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells.

机构信息

Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, Aix-Marseille Univ, Marseille, France.

Faculté de Médecine de Tunis, LR99ES10 Laboratoire de Génétique Humaine, Université de Tunis El Manar, Tunis, Tunisia.

出版信息

EMBO Mol Med. 2019 Oct;11(10):e9930. doi: 10.15252/emmm.201809930. Epub 2019 Sep 2.

DOI:10.15252/emmm.201809930
PMID:31476112
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6783652/
Abstract

Therapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSCs may represent a reservoir of therapeutic target to improve cancer treatment. Here, we carried out a genome-wide RNA interference screen to identify genes that regulate breast CSCs-fate (bCSC). Using an interactome/regulome analysis, we integrated screen results in a functional mapping of the CSC-related processes. This network analysis uncovered potential therapeutic targets controlling bCSC-fate. We tested a panel of 15 compounds targeting these regulators. We showed that mifepristone, salinomycin, and JQ1 represent the best anti-bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/JQ1 association to deplete the bCSC population. Treatment of primary breast cancer xenografts with this combination reduced the tumor-initiating cell population and limited metastatic development. The clinical relevance of our findings was reinforced by an association between the expression of the bCSC-related networks and patient prognosis. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer.

摘要

治疗抵抗是肿瘤学中的一个主要临床挑战。有证据表明癌症干细胞（CSC）是肿瘤进化的驱动因素。因此，CSC 所特有的关键干性特征可能代表了改善癌症治疗的治疗靶点的储备库。在这里，我们进行了全基因组 RNA 干扰筛选，以鉴定调节乳腺 CSC 命运（bCSC）的基因。通过互作体/调控网络分析，我们将筛选结果整合到 CSC 相关过程的功能映射中。该网络分析揭示了控制 bCSC 命运的潜在治疗靶点。我们测试了针对这些调节剂的 15 种化合物的面板。我们表明米非司酮、杀稻瘟菌素和 JQ1 代表了最佳的抗 bCSC 活性。组合测定显示杀稻瘟菌素/JQ1 联合使用具有协同作用，可以耗尽 bCSC 群体。用该组合治疗原发性乳腺癌异种移植物可减少肿瘤起始细胞群体并限制转移发展。bCSC 相关网络的表达与患者预后之间的关联增强了我们研究结果的临床相关性。用杀稻瘟菌素/JQ1 联合靶向 bCSC 为治疗乳腺癌提供了一种新的治疗方法的基础。

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