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

EMBO Molecular Medicine

Maher Kharrat¹  Hayet Douik¹  Abigaelle Gros²  Emmanuelle Charafe‐Jauffret²  Julien Wicinski²  Abir Arfaoui²  Candi Léonard‐Stumpf²  Violette Azzoni²  Manon Macario²  Christophe Ginestier²  Anthony Bal²  Daniel Birnbaum³  Francois Bertucci³  Pascal Finetti³  Ghislain Bidaut⁴  Claire Rioualen⁴  Rémy Castellano⁵  Yves Collette⁵  Emmanuelle Josselin⁵  Guillaume Pinna⁶  Sylvain Lossy⁶ 

[1] Faculté de Médecine de Tunis LR99ES10 Laboratoire de Génétique Humaine Université de Tunis El Manar Tunis Tunisia;Inserm CNRS Institut Paoli‐Calmettes CRCM Epithelial Stem Cells and Cancer Lab Aix‐Marseille Univ Marseille France;Inserm CNRS Institut Paoli‐Calmettes CRCM Molecular Oncology “Equipe labellisée Ligue Contre le Cancer” Aix‐Marseille Univ Marseille France;Inserm CNRS Institut Paoli‐Calmettes CRCM Plateform Integrative Bioinformatics, Cibi Aix‐Marseille Univ Marseille France;Inserm CNRS Institut Paoli‐Calmettes CRCM TrGET Plateform Aix‐Marseille Univ Marseille France;Plateforme ARN Interférence Service de Biologie Intégrative et de Génétique Moléculaire (SBIGeM) I2BC, CEA, CNRS Université Paris‐Saclay Gif‐sur‐Yvette France;

关键词: breast cancer;    cancer stem cells;    JQ1;    RNAi screen;    salinomycin;   

DOI  :  10.15252/emmm.201809930

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown