A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells
Abir Arfaoui
(1, 2)
,
Claire Rioualen
(1)
,
Violette Azzoni
(1)
,
Guillaume Pinna
(3, 4)
,
Pascal Finetti
(1)
,
Julien Wicinski
(1)
,
Emmanuelle Josselin
(1)
,
Manon Macario
(1)
,
Rémy Castellano
(1)
,
Candi Léonard-Stumpf
(1)
,
Anthony Bal
(1)
,
Abigaelle Gros
(1)
,
Sylvain Lossy
(5)
,
Maher Kharrat
(2)
,
Yves Collette
(6)
,
François Bertucci
(6)
,
Daniel Birnbaum
(1)
,
Hayet Douik
(7, 2)
,
Ghislain Bidaut
(1)
,
Emmanuelle Charafe-Jauffret
(1)
,
Christophe Ginestier
(1)
Violette Azzoni
- Fonction : Auteur
- PersonId : 796974
- ORCID : 0000-0003-1438-3076
Pascal Finetti
- Fonction : Auteur
- PersonId : 753338
- IdHAL : pascal-finetti
- ORCID : 0000-0002-2674-3123
Rémy Castellano
- Fonction : Auteur
- PersonId : 759966
- ORCID : 0000-0002-0152-985X
Yves Collette
- Fonction : Auteur
- PersonId : 752645
- IdHAL : yves-collette
- ORCID : 0000-0001-5359-7099
- IdRef : 070509891
François Bertucci
- Fonction : Auteur
- PersonId : 753650
- IdHAL : francois-bertucci
- ORCID : 0000-0002-0157-0959
Daniel Birnbaum
- Fonction : Auteur
- PersonId : 834190
Emmanuelle Charafe-Jauffret
- Fonction : Auteur
- PersonId : 757496
- ORCID : 0000-0002-0286-1299
- IdRef : 188353305
Christophe Ginestier
- Fonction : Auteur
- PersonId : 753078
- IdHAL : christophe-ginestier
- ORCID : 0000-0002-7477-3837
- IdRef : 092140866
Résumé
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.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells
|
Résumé |
en
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.
|
Auteur(s) |
Abir Arfaoui
1, 2
, Claire Rioualen
1
, Violette Azzoni
1
, Guillaume Pinna
3, 4
, Pascal Finetti
1
, Julien Wicinski
1
, Emmanuelle Josselin
1
, Manon Macario
1
, Rémy Castellano
1
, Candi Léonard-Stumpf
1
, Anthony Bal
1
, Abigaelle Gros
1
, Sylvain Lossy
5
, Maher Kharrat
2
, Yves Collette
6
, François Bertucci
6
, Daniel Birnbaum
1
, Hayet Douik
7, 2
, Ghislain Bidaut
1
, Emmanuelle Charafe-Jauffret
1
, Christophe Ginestier
1
1
CRCM -
Centre de Recherche en Cancérologie de Marseille
( 179570 )
- 27 bd Leï Roure, BP 300059
13273 Marseille Cedex 09
- France
2
UTM -
Université de Tunis El Manar
( 207896 )
- Campus Universitaire Farhat Hached B.P. n° 94 - ROMMANA 1068 Tunis
- Tunisie
3
I2BC -
Institut de Biologie Intégrative de la Cellule
( 414518 )
- Bâtiment 21, 1 avenue de la Terrasse, 91198 Gif/Yvette cedex
- France
4
PARI -
PARi
( 460091 )
- I2BC, Bâtiment 21, 1 avenue de la Terrasse, 91198 Gif/Yvette cedex
- France
5
SBIGeM -
Service de Biologie Intégrative et Génétique Moléculaire
( 40491 )
- CEA Saclay 91191 Gif sur Yvette cedex
- France
6
IPC -
Institut Paoli-Calmettes
( 301325 )
- 232 Boulevard de Sainte-Marguerite
13009 Marseille
- France
7
Institut Salah Azaiz
( 520044 )
- Tunisie
|
Date de publication électronique |
2019-09-02
|
Date de publication |
2019
|
Page/Identifiant |
e9930
|
Langue du document |
Anglais
|
Nom de la revue |
|
Numéro |
10
|
Volume |
11
|
Audience |
Internationale
|
Comité de lecture |
Oui
|
Vulgarisation |
Non
|
Domaine(s) |
|
Mots-clés |
en
Regenerative Medicine, Chemical Biology, breast cancer, JQ1, cancer stem cells, salinomycin, RNAi screen
|
DOI | 10.15252/emmm.201809930 |
Pubmed Id | 31476112 |
Origine :
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