Unraveling Heterogeneity in Epithelial Cell Fates of the Mammary Gland and Breast Cancer - PubMed (original) (raw)

Review

Unraveling Heterogeneity in Epithelial Cell Fates of the Mammary Gland and Breast Cancer

Alexandr Samocha et al. Cancers (Basel). 2019.

Abstract

Fluidity in cell fate or heterogeneity in cell identity is an interesting cell biological phenomenon, which at the same time poses a significant obstacle for cancer therapy. The mammary gland seems a relatively straightforward organ with stromal cells and basal- and luminal- epithelial cell types. In reality, the epithelial cell fates are much more complex and heterogeneous, which is the topic of this review. Part of the complexity comes from the dynamic nature of this organ: the primitive epithelial tree undergoes extensively remodeling and expansion during puberty, pregnancy, and lactation and, unlike most other organs, the bulk of mammary gland development occurs late, during puberty. An active cell biological debate has focused on lineage commitment to basal- and luminal- epithelial cell fates by epithelial progenitor and stem cells; processes that are also relevant to cancer biology. In this review, we discuss the current understanding of heterogeneity in mammary gland and recent insights obtained through lineage tracing, signaling assays, and organoid cultures. Lastly, we relate these insights to cancer and ongoing efforts to resolve heterogeneity in breast cancer with single-cell RNAseq approaches.

Keywords: 3D cultures; breast cancer; cell fate; heterogeneity; mammary gland; organoids; signaling; single-cell RNAseq.

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Conflict of interest statement

Jeroen Roose is a co-founder and scientific advisor of Seal Biosciences, Inc. and on the scientific advisory committee for the Mark Foundation for Cancer Research. The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Schematic of mouse mammary gland development during puberty. During puberty, the rudimentary duct undergoes significant expansion, resulting in the formation of bulbous multilayered structures called terminal end buds (TEBs). These TEBs are the proliferative centers that drive elongation, bifurcation, and branching of ducts until the entirety of the mammary fat pad is filled, thereby creating the mature epithelial tree.

Figure 2

Figure 2

Schematic of three-dimensional spheroid cultures of mammary gland tissue. The discovery of Matrigel by Orkin and colleagues [26] enabled cell biological studies by many research groups with three-dimensional (3D) spheroid cultures of mammary gland tissue in vitro. Plating of digested MEC clusters aided the identification of restricted luminal- or basal-cells and bipotent progenitors in 3D, while further digestion into single mammary epithelial cells and plating into colony-forming assays provided information on the proliferative capacity.

Figure 3

Figure 3

Schematic of the developmental hierarchy in the mammary gland. It should be explicitly stressed that Figure 3 is a model. In this hierarchy, mature luminal cells and mature basal cells are maintained by lineage-restricted, unipotent progenitors, which are replenished by multipotent stem cells that are present during embryogenesis.

Figure 4

Figure 4

Pipeline of mammary gland organoid cultures. Submerging the Matrigel droplet with growth medium containing Wnt and R-Spondin ligands enables sustained maintenance of stem cell function and allows for functional studies on mammary stem cells (MaSCs) in these 3D cultures.

Figure 5

Figure 5

Pipeline of scRNAseq to resolve cellular heterogeneity with novel sequencing techniques. Processing mammary gland tissue of breast cancers into single-cell droplets coupled to single-cell RNA sequencing (scRNAseq) and data analysis (e.g., tSNE plots) allows for high resolution investigation of different cell types on the basis of individual cell transcriptome.

Figure 6

Figure 6

Organoids, scRNAseq, and other technologies to resolve cellular heterogeneity. Combination of different platforms such as organoids and scRNAseq but also mouse models, lineage tracing, and patient-centric assays will likely each make important contributions to resolve cellular heterogeneity in the mammary gland and in breast cancer.

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