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

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

  • EMBO Mol Med. 2019 Oct;11(10):e9930. doi: 10.15252/emmm.201809930.
Abir Arfaoui 1 2 3,  Claire Rioualen 4,  Violette Azzoni 1,  Guillaume Pinna 5,  Pascal Finetti 6,  Julien Wicinski 1,  Emmanuelle Josselin 7,  Manon Macario 1,  Rémy Castellano 7,  Candi Léonard-Stumpf 1,  Anthony Bal 1,  Abigaelle Gros 1,  Sylvain Lossy 5,  Maher Kharrat 2,  Yves Collette 7,  Francois Bertucci 6,  Daniel Birnbaum 6,  Hayet Douik 2 3,  Ghislain Bidaut 4,  Emmanuelle Charafe-Jauffret 1,  Christophe Ginestier 1
Affiliations

Affiliations

  • 1 Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, Aix-Marseille Univ, Marseille, France.
  • 2 Faculté de Médecine de Tunis, LR99ES10 Laboratoire de Génétique Humaine, Université de Tunis El Manar, Tunis, Tunisia.
  • 3 Service de Biologie Clinique, Institut Salah Azaiz, Tunis, Tunisia.
  • 4 Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Plateform Integrative Bioinformatics, Cibi, Aix-Marseille Univ, Marseille, France.
  • 5 Plateforme ARN Interférence, Service de Biologie Intégrative et de Génétique Moléculaire (SBIGeM), I2BC, CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette, France.
  • 6 Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Molecular Oncology "Equipe labellisée Ligue Contre le Cancer", Aix-Marseille Univ, Marseille, France.
  • 7 Inserm, CNRS, Institut Paoli-Calmettes, CRCM, TrGET Plateform, Aix-Marseille Univ, Marseille, France.
PMID: 31476112 DOI: 10.15252/emmm.201809930
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.

Keywords

JQ1; RNAi screen; breast cancer; cancer stem cells; salinomycin.

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