RT Journal Article
SR Electronic
T1 Heterogeneity of normal human breast stem and progenitor cells as revealed by transcriptional profiling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 109751
DO 10.1101/109751
A1 Justin A. Colacino
A1 Ebrahim Azizi
A1 Michael D. Brooks
A1 Shamileh Fouladdel
A1 Sean P. McDermott
A1 Michael Lee
A1 David Hill
A1 Maureen A. Sartor
A1 Laura S. Rozek
A1 Max S. Wicha
YR 2017
UL http://biorxiv.org/content/early/2017/02/18/109751.abstract
AB During development and pregnancy, the human mammary gland undergoes extensive remodeling in processes driven by populations of stem and progenitor cells. We recently reported that breast cancers are also hierarchically organized and driven by distinct populations of cancer stem cells characterized as CD44+CD24low/− or by expression of Aldehyde dehydrogenase (ALDH). These sets of markers identify largely non-overlapping mesenchymal and epithelial populations, each of which is capable of tumor initiation when transplanted into immunosuppressed mice. Less is known about these two populations, individually or their overlap, in the normal human mammary gland. The goal of this study was to understand the biology of the ALDH+ and CD44+CD24− populations in the normal human breast, using flow cytometry based sorting paired with functional ex vivo analyses, RNA-sequencing, and single cell RNA expression profiling. ALDH+ cells and ALDH−CD44+CD24− cells, generally, have epithelial-like and mesenchymal-like characteristics, respectively. Despite this, there are substantial similarities in the biological pathways activated in both populations when compared to differentiated cells. Additionally, we found a substantial proportion of cells that simultaneously express ALDH+ and CD44+CD24− whose abundance varies between individuals. At the single cell level, these cells have the greatest mammosphere forming capacity and express high levels of stemness and EMT-associated genes including ID1, SOX2, TWIST1, and ZEB2. Through unbiased analysis of individual ALDH+ cells, we find cells with either epithelial or mesenchymal expression phenotypes. We also identify a subpopulation of cells with a hybrid epithelial/mesenchymal expression phenotype that overexpress genes associated with aggressive triple negative breast cancers. These results highlight the utility of single cell analyses to characterize tissue heterogeneity, even in marker enriched cell populations, and further identifies the genes and pathways that define this heterogeneity.