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Cited by 1,775Single-cell and spatial transcriptomicsBreast Cancer Treatment StudiesCancer Immunotherapy and Biomarkers

A single-cell and spatially resolved atlas of human breast cancers

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Wu, Sunny Z., Al-Eryani, Ghamdan, Roden, Daniel Lee, Junankar, Simon, Harvey, Kate, Andersson, Alma, Thennavan, Aatish, Wang, Chenfei +32 more·2021·Nature Genetics
DOI 10.1038/s41588-021-00911-1PMC PMC9044823
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Abstract

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.

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  • The proliferation score, defined based on S-phase genes and G2/M cell-cycle genes, was used to identify proliferative cells, given that senescent cells exhibit G1-arrest.

    “The proliferation score, defined based on S-phase genes and G2/M cell-cycle genes [24], was used to identify proliferative cells, given that senescent cells exhibit G1-arrest.”

    From Ensemble of Time-Evolving SASP Gene Sets Identifies IGFBP7 and CDKN1A as a Potential Marker Pair for Senescent Fibroblast Subpopulations Across Tissues (2026) · cites this paper as [24]

    The Methods section, “Calculating Proliferation and differentiation scores” (page unavailable), confirms that the paper calculated a proliferation score. It defines the score as the average normalized expression of 11 specified genes, not explicitly as a score based on S-phase and G2/M gene sets. The citation is attached to the score definition; the citing authors’ subsequent use of the score and G1-arrest rationale are not attributed to this source. (LLM, conf=0.85)

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Authors
Wu, S. Z., Al-Eryani, G., Roden, D. L., Junankar, S., Harvey, K., Andersson, A., Thennavan, A., Wang, C., Torpy, J. R., Bartonicek, N., Wang, T., Larsson, L., Kaczorowski, D., Weisenfeld, N. I., Uytingco, C. R., Chew, J. G., Bent, Z. W., Chan, C.-L., Gnanasambandapillai, V., Dutertre, C.-A., Gluch, L., Hui, M. N., Beith, J., Parker, A., Robbins, E., Segara, D., Cooper, C., Mak, C., Chan, B., Warrier, S., Ginhoux, F., Millar, E., Powell, J. E., Williams, S. R., Liu, X. S., O’Toole, S., Lim, E., Lundeberg, J., Perou, C. M., & Swarbrick, A.
Affiliations
  • Garvan Institute of Medical Research (AU)
  • Science for Life Laboratory (SE)
  • University of North Carolina at Chapel Hill (US)
  • Harvard University (US)
  • 10X Genomics (United States) (US)
  • Inserm (FR)
  • Chris O’Brien Lifehouse (AU)
  • UNSW Sydney (AU)
  • Royal Prince Alfred Hospital (AU)
  • St Vincent's Hospital Sydney (AU)
  • The University of Queensland (AU)
  • The University of Sydney (AU)
  • Agency for Science, Technology and Research (SG)
Corresponding author
Swarbrick, Alexander
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-09
Volume
53
Issue
9
Pages
1334-1347
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-021-00911-1
PMC
PMC9044823
OpenAlex
W3198511950
Cited by
1,775
References
11
Citations by year
2026: 459 · 2025: 430 · 2024: 424 · 2023: 316 · 2022: 140 · 2021: 6
FWCI
72.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • National Breast Cancer Foundation (IIRS-19-106, IIRS-19-084, PRAC 16-006)
  • Petre Foundation
  • Department of Health | National Health and Medical Research Council
  • The White Butterfly Foundation The Sydney Breast Cancer Foundation John McMurtrie (AM) and Deborah McMurtrie
  • Breast Cancer Research Foundation
  • The Sydney Breast Cancer Foundation The Family and Friends of Michael O'Sullivan
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
breast cancer, tumor heterogeneity, tumor microenvironment, macrophages, mesenchymal cells, CITE-seq, spatial transcriptomics, single-cell RNA sequencing, prognosis
MeSH terms
B-Lymphocytes, Breast Neoplasms, Female, Humans, Macrophages, Membrane Proteins, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Sequence Analysis, RNA, CD8-Positive T-Lymphocytes, Myeloid Cells, Tumor Suppressor Proteins, Endothelial Cells, Single-Cell Analysis, Tumor Microenvironment, Transcriptome, B7-H1 Antigen

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