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Heterogeneity of normal human breast stem and progenitor cells as revealed by transcriptional profiling

Justin A. Colacino, Ebrahim Azizi, Michael D. Brooks, Shamileh Fouladdel, Sean P. McDermott, Michael Lee, David Hill, Maureen A. Sartor, Laura S. Rozek, Max S. Wicha
doi: https://doi.org/10.1101/109751
Justin A. Colacino
1Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
2Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
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  • For correspondence: colacino@umich.edu mwicha@med.umich.edu
Ebrahim Azizi
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Michael D. Brooks
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Shamileh Fouladdel
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Sean P. McDermott
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Michael Lee
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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David Hill
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Maureen A. Sartor
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
5Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
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Laura S. Rozek
1Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
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Max S. Wicha
3Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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  • For correspondence: colacino@umich.edu mwicha@med.umich.edu
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Abstract

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.

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Posted February 18, 2017.
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Heterogeneity of normal human breast stem and progenitor cells as revealed by transcriptional profiling
Justin A. Colacino, Ebrahim Azizi, Michael D. Brooks, Shamileh Fouladdel, Sean P. McDermott, Michael Lee, David Hill, Maureen A. Sartor, Laura S. Rozek, Max S. Wicha
bioRxiv 109751; doi: https://doi.org/10.1101/109751
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Heterogeneity of normal human breast stem and progenitor cells as revealed by transcriptional profiling
Justin A. Colacino, Ebrahim Azizi, Michael D. Brooks, Shamileh Fouladdel, Sean P. McDermott, Michael Lee, David Hill, Maureen A. Sartor, Laura S. Rozek, Max S. Wicha
bioRxiv 109751; doi: https://doi.org/10.1101/109751

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