ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Emmanuelle Charafe-Jauffret (1, 2) , Christophe Ginestier (1) , François Bertucci (1) , Olivier Cabaud (1) , Julien Wicinski (1) , Pascal Finetti (2, 1) , Emmanuelle Josselin (3) , José Adelaïde (1) , Tien-Tuan Nguyen (4) , Florence Monville (5) , Jocelyne Jacquemier (6, 1) , Jeanne Thomassin-Piana , Guillaume Pinna (7) , Aurelie Jalaguier , Eric Lambaudie (8) , Gilles Houvenaeghel (2, 9) , Luc Xerri (10) , Annick Harel-Bellan (11) , Max Chaffanet (1) , Patrice Viens (12, 1) , Daniel Birnbaum (1)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 IPC - Institut Paoli-Calmettes
3 CIML - Centre d'Immunologie de Marseille - Luminy
4 IL - Institut Langevin - Ondes et Images (UMR7587)
5 Inserm U599/IPC - Cancérologie
6 Département de biopathologie
7 I2BC - Institut de Biologie Intégrative de la Cellule
8 Service d'Oncologie Chirurgicale
9 Paoli Calmette - Département de chirurgie Paoli Calmette
10 Département de Biopathologie
11 LEC - Laboratoire Epigénétique et Cancer
12 Service d'Oncologie Médicale

Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor-derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer. (C) 2013 AACR.

Domaines: Cancer; Biologie cellulaire

Emmanuelle Charafe-Jauffret, Christophe Ginestier, François Bertucci, Olivier Cabaud, Julien Wicinski, et al.. ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program. Cancer Research, 2013, 73 (24), pp.7290-7300. ⟨10.1158/0008-5472.CAN-12-4704⟩. ⟨hal-01431937⟩