Construction of developmental lineage relationships in the mouse mammary gland by single-cell RNA profiling

Abstract

The mammary epithelium comprises two primary cellular lineages, but the degree of heterogeneity within these compartments and their lineage relationships during development remain an open question. Here we report single-cell RNA profiling of mouse mammary epithelial cells spanning four developmental stages in the post-natal gland. Notably, the epithelium undergoes a large-scale shift in gene expression from a relatively homogeneous basal-like program in pre-puberty to distinct lineage-restricted programs in puberty. Interrogation of single-cell transcriptomes reveals different levels of diversity within the luminal and basal compartments, and identifies an early progenitor subset marked by CD55. Moreover, we uncover a luminal transit population and a rare mixed-lineage cluster amongst basal cells in the adult mammary gland. Together these findings point to a developmental hierarchy in which a basal-like gene expression program prevails in the early post-natal gland prior to the specification of distinct lineage signatures, and the presence of cellular intermediates that may serve as transit or lineage-primed cells.

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

“…4A). Concomitantly with the scRNAseq data, FACS analysis of the cancer epithelial cells revealed that Elf5 forced differentiation of the luminal progenitors, defined by a decrease in the proportion of Sca1 low /CD49b + progenitor cells 2 within the luminal (EpCam+/CD49f+) population (Fig 2D).We plotted each of our epithelial cells against the gene expression signatures for the epithelial cell lineages of the normal mammary gland23 to reveal the phenotypic similarity of our MMTV-PyMT epithelial cell clusters to those lineages currently recognised. Ternary plots shown inFig.…”

“…0 3). We used the mammary gland hierarchy gene signature 23 To gain insights in this definition, we used GSVA 26…”

Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

“…Despite ongoing discussion in this area, a considerable body of work supports specific mammary populations as the candidate cells‐of‐origin for breast cancer subtypes. Finally, techniques such as scRNA‐seq and mass cytometry (CyTOF) are exposing heterogeneity within the basal and luminal compartments (Bach et al , ; Pal et al , ; Giraddi et al , ; Nguyen et al , ), indicating the necessity of further dissecting precursor–progeny relationships and developmental correlates of tumorigenesis.…”

Universal principles of lineage architecture and stem cell identity in renewing tissues

“…Note that multiple apexes of a lineage can in principle exist (see Fig. 2), as is for instance conjectured for mouse mammary epithelium lineage (23).…”