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A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast.

ABSTRACT: To examine global changes in breast heterogeneity across different states, we determined the single-cell transcriptomes of > 340,000 cells encompassing normal breast, preneoplastic BRCA1^+/- tissue, the major breast cancer subtypes, and pairs of tumors and involved lymph nodes. Elucidation of the normal breast microenvironment revealed striking changes in the stroma of post-menopausal women. Single-cell profiling of 34 treatment-naive primary tumors, including estrogen receptor (ER)⁺ , HER2⁺ , and triple-negative breast cancers, revealed comparable diversity among cancer cells and a discrete subset of cycling cells. The transcriptomes of preneoplastic BRCA1^+/- tissue versus tumors highlighted global changes in the immune microenvironment. Within the tumor immune landscape, proliferative CD8⁺ T cells characterized triple-negative and HER2⁺ cancers but not ER⁺ tumors, while all subtypes comprised cycling tumor-associated macrophages, thus invoking potentially different immunotherapy targets. Copy number analysis of paired ER⁺ tumors and lymph nodes indicated seeding by genetically distinct clones or mass migration of primary tumor cells into axillary lymph nodes. This large-scale integration of patient samples provides a high-resolution map of cell diversity in normal and cancerous human breast.

SUBMITTER: Pal B

PROVIDER: S-EPMC8167363 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast.

Pal Bhupinder B Chen Yunshun Y Vaillant François F Capaldo Bianca D BD Joyce Rachel R Song Xiaoyu X Bryant Vanessa L VL Penington Jocelyn S JS Di Stefano Leon L Tubau Ribera Nina N Wilcox Stephen S Mann Gregory B GB Papenfuss Anthony T AT Lindeman Geoffrey J GJ Smyth Gordon K GK Visvader Jane E JE

The EMBO journal 20210505 11

To examine global changes in breast heterogeneity across different states, we determined the single-cell transcriptomes of > 340,000 cells encompassing normal breast, preneoplastic BRCA1<sup>+/-</sup> tissue, the major breast cancer subtypes, and pairs of tumors and involved lymph nodes. Elucidation of the normal breast microenvironment revealed striking changes in the stroma of post-menopausal women. Single-cell profiling of 34 treatment-naive primary tumors, including estrogen receptor (ER)<su ...[more]

PMID: 33950524

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Project description:BackgroundThe interface zone, area around invasive carcinoma, can be thought of as the actual tissue of the tumor microenvironment with precedent alterations for tumor invasion. However, the heterogeneity and characteristics of the microenvironment in the interface area have not yet been thoroughly explored.MethodsFor in vitro studies, single-cell RNA sequencing (scRNA-seq) was used to characterize the cells from the tumor zone, the normal zone and the interface zone with 5-mm-wide belts between the tumor invasion front and the normal zone. Through scRNA-seq data analysis, we compared the cell types and their transcriptional characteristics in the different zones. Pseudotime, cell-cell communication and pathway analysis were performed to characterize the zone-specific microenvironment. Cell proliferation, wound healing and clone formation experiments explored the function of differentially expressed gene BMPR1B, which were confirmed by tumor models in vivo.ResultsAfter screening, 88,548 high-quality cells were obtained and identified. Regulatory T cells, M2 macrophages, angiogenesis-related mast cells, stem cells with weak DNA repair ability, endothelial cells with angiogenic activity, fibroblasts with collagen synthesis and epithelial cells with proliferative activity form a unique tumorigenic microenvironment in the interface zone. Cell-cell communication analysis revealed that there are special ligand-receptor pairs between different cell types in the interface zone, which protects endothelial cell apoptosis and promotes epithelial cell proliferation and migration, compared to the normal zone. Compared with the normal zone, the highly expressed BMPR1B gene promotes the tumorigenic ability of cancer cells in the interface zone.ConclusionsOur work identified a unique tumorigenic microenvironment of the interface zone and allowed for deeper insights into the tumor microenvironment of breast cancer that will serve as a helpful resource for advancing breast cancer diagnosis and therapy.

Dataset Information

A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast.

Publications

A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast.

Similar Datasets

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