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
  • 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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