Heterogeneity of Human Breast Stem and Progenitor Cells as Revealed by Transcriptional Profiling

Abstract

SummaryDuring development, the mammary gland undergoes extensive remodeling driven by stem cells. Breast cancers are also hierarchically organized and driven by cancer stem cells characterized by CD44+CD24low/− or aldehyde dehydrogenase (ALDH) expression. These markers identify mesenchymal and epithelial populations both capable of tumor initiation. Less is known about these populations in non-cancerous mammary glands. From RNA sequencing, ALDH+ and ALDH−CD44+CD24− human mammary cells have epithelial-like and mesenchymal-like characteristics, respectively, with some co-expressing ALDH+ and CD44+CD24− by flow cytometry. At the single-cell level, these cells have the greatest mammosphere-forming capacity and express high levels of stemness and epithelial-to-mesenchymal transition-associated genes including ID1, SOX2, TWIST1, and ZEB2. We further identify single ALDH+ cells with a hybrid epithelial/mesenchymal phenotype that express genes associated with aggressive triple-negative breast cancers. These results highlight single-cell analyses to characterize tissue heterogeneity, even in marker-enriched populations, and identify genes and pathways that define this heterogeneity.

Towards understanding cancer stem cell heterogeneity in the tumor microenvironment

“…Our model predicts that mesenchymal-like CSCs localize at the invasive edge of the tumor and hybrid E/M CSCs localize in the tumor interior. This prediction agrees well, at least qualitatively, with recent observations in human breast carcinoma tissue, where CD44+/CD24-cells (mesenchymal CSCs) were present at the tumor invasive edge, while ALDH1+ cells (hybrid E/M CSCs (20,31)) were present in the interior of the tumor (9). However, we acknowledge that our First, we assumed a spatial profile of TGF-β based on its secretion from stromal cells; however, there may be local variations in TGF-β signal intensity due to a variety of mechanical and/or chemical stimuli, including its secretion by cancer cells.…”

“…1A). Follow-up studies have characterized these ALDH1+ cells as showing a hybrid E/M, and not a purely epithelial, signature (31).…”

Potential application of cell reprogramming techniques for cancer research

“…This technology allows the identification of the cellular subpopulations and the delineation of novel cell markers in the hematopoietic [71], respiratory [72], hepatobiliary [73], and pancreatic [74, 75] lineages, as well as in the intestine [76]. Recent progress in single-cell RNA sequencing led to the identification of the heterogeneous origins of CSCs in gliomas [77], breast cancers [78], myeloid leukemias [79], bladder cancers [80], and colorectal cancers [81]. These heterogeneities stem from the original unidentified subpopulations that arise during the step of induction of cancer-specific iPSCs.…”

A dormant sub-population expressing interleukin-1 receptor characterises anti-estrogen resistant ALDH+ breast cancer stem cells

“…This idea is supported by data from AI-induced dormant tumours that express increased levels of ALDH1A1 and ALDH1A3 genes. Recently, single-cell RNA profiling of normal breast samples identified four cell clusters within the ALDH+ cell population (Colacino et al, 2018). Interestingly, Population B resembles cluster 3 identified in this publication, which was characterized by high expression of mesenchymal markers, including SNAI2, and low expression of proliferative genes, such as KI67, PCNA, CCND1.…”