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

被引：29

作者：

Arfaoui, Abir ^{[1
,2
,3
]}

Rioualen, Claire ^{[4
]}

Azzoni, Violette ^{[1
]}

Pinna, Guillaume ^{[5
]}

Finetti, Pascal ^{[6
]}

Wicinski, Julien ^{[1
]}

Josselin, Emmanuelle ^{[7
]}

Macario, Manon ^{[1
]}

Castellano, Remy ^{[7
]}

Leonard-Stumpf, Candi ^{[1
]}

Bal, Anthony ^{[1
]}

Gros, Abigaelle ^{[1
]}

Lossy, Sylvain ^{[5
]}

Kharrat, Maher ^{[2
]}

Collette, Yves ^{[7
]}

Bertucci, Francois ^{[6
]}

Birnbaum, Daniel ^{[6
]}

Douik, Hayet ^{[2
,3
]}

Bidaut, Ghislain ^{[4
]}

Charafe-Jauffret, Emmanuelle ^{[1
]}

Ginestier, Christophe ^{[1
]}

机构：

[1] Aix Marseille Univ, Inst Paoli Calmettes, Epithelial Stem Cells & Canc Lab, CRCM,Inserm, Marseille, France

[2] Univ Tunis El Manar, Fac Med Tunis, Lab Genet Humaine LR99ES10, Tunis, Tunisia

[3] Inst Salah Azaiz, Serv Biol Clin, Tunis, Tunisia

[4] Aix Marseille Univ, Cibi, Plateform Integrat Bioinformat, Inserm,CNRS,Inst Paoli Calmettes,CRCM, Marseille, France

[5] Univ Paris Saclay, Serv Biol Integrat & Genet Mol SBIGeM, CEA, Plateforme ARN Interference,CNRS, Gif Sur Yvette, France

[6] Aix Marseille Univ, Mol Oncol Equipe Labellisee Ligue Contre Canc, CRCM, Inserm,CNRS,Inst Paoli Calmettes, Marseille, France

[7] Aix Marseille Univ, Inst Paoli Calmettes, TrGET Plateform, CRCM,Inserm,CNRS, Marseille, France

来源：

EMBO MOLECULAR MEDICINE | 2019年 / 11卷 / 10期

关键词：

breast cancer; cancer stem cells; JQ1; RNAi screen; salinomycin; SUPER-ENHANCER; INHIBITION; RESISTANCE; FATE; EVOLUTIONARY; SALINOMYCIN; SWITCH;

D O I：

10.15252/emmm.201809930

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：18

共 43 条

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