ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program
Menée à l'aide de xénogreffes dérivées de tumeurs primitives du sein, cette étude française met en évidence le role d'un programme transcriptionnel de 19 gènes dans la régulation des cellules souches cancéreuses surexprimant ALDH1
Cancer stem-like cells (CSC) have been widely studied but their clinical relevance has yet to be established in breast cancer (BC). Here we report the establishment of primary breast tumor-derived xenografts (PDXs) that encompass the main diversity of human BC and retain the major clinicopathological features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs which predicted prognosis in patients. The xenografts we developed demonstrated a hierarchical cell organization of BC 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 breast cancer patients.