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

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 anal...

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Vydáno v:	Nature genetics Ročník 53; číslo 9; s. 1334 - 1347
Hlavní autoři:	Wu, Sunny Z., Al-Eryani, Ghamdan, Roden, Daniel Lee, Junankar, Simon, Harvey, Kate, Andersson, Alma, Thennavan, Aatish, Wang, Chenfei, Torpy, James R., Bartonicek, Nenad, Wang, Taopeng, Larsson, Ludvig, Kaczorowski, Dominik, Weisenfeld, Neil I., Uytingco, Cedric R., Chew, Jennifer G., Bent, Zachary W., Chan, Chia-Ling, Gnanasambandapillai, Vikkitharan, Dutertre, Charles-Antoine, Gluch, Laurence, Hui, Mun N., Beith, Jane, Parker, Andrew, Robbins, Elizabeth, Segara, Davendra, Cooper, Caroline, Mak, Cindy, Chan, Belinda, Warrier, Sanjay, Ginhoux, Florent, Millar, Ewan, Powell, Joseph E., Williams, Stephen R., Liu, X. Shirley, O’Toole, Sandra, Lim, Elgene, Lundeberg, Joakim, Perou, Charles M., Swarbrick, Alexander
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.09.2021 Nature Publishing Group
Témata:	631/67/1347 631/67/327 Agriculture Animal Genetics and Genomics B-Lymphocytes - immunology B7-H1 Antigen - genetics Biomarkers, Tumor - genetics Biomedical and Life Sciences Biomedicine Breast cancer Breast Neoplasms - genetics Breast Neoplasms - immunology Breast Neoplasms - pathology Cancer Research Cancer therapies Care and treatment CD8-Positive T-Lymphocytes - immunology Cell differentiation Cell surface Composition Datasets Development and progression Ecotypes Endothelial Cells - metabolism Epitopes Female Gene expression Gene Expression Regulation, Neoplastic - genetics Gene Function Genetic aspects Genetic transcription Health aspects Heterogeneity Histology Human Genetics Humans Immunoregulation Macrophages Macrophages - cytology Macrophages - immunology Membrane Proteins - genetics Mesenchyme Myeloid Cells - immunology Myeloid Cells - metabolism PD-L1 protein Prognosis RNA sequencing Sequence Analysis, RNA Single-Cell Analysis Taxonomy Transcription Transcriptome - genetics Transcriptomes Tumor Microenvironment Tumor Suppressor Proteins - genetics Tumors Australia
ISSN:	1061-4036, 1546-1718, 1546-1718
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Shrnutí:	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. A multi-omic atlas of breast cancers, integrating single-cell RNA sequencing, spatial transcriptomics and immunophenotyping, identifies nine ecotypes associated with cellular heterogeneity and prognosis.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 AS conceived the project and directed the study with input from all authors. SZW, AS, DR, GA-E and SJ wrote the manuscript with input from all authors. EL, SW, MNH, BC, CC, CM, DS, ER, AP, JB, SOT, EM and LG contributed to experimental design, procured patient tumor tissue and assisted with interpreting data. SZW, GA-E & KH performed single cell captures and KH analysed all clinical information. SZW, KH and GA-E optimized and performed tumor dissociation experiments. GA-E optimised and performed antibody staining for CITE-Seq experiments. NB and GA-E performed the CITE-Seq data processing. CL-C and SZW performed scRNA-Seq experiments on the Chromium Controller. CL-C helped perform the next-generation sequencing of the scRNA-Seq libraries. SZW performed the pre-processing, data-integration and reclustering steps for the scRNA-Seq data. JT performed the analysis and benchmarking of inferCNV. AT and CMP led the development of scSubtype. DR interpreted and led the analyses for breast cancer gene module analyses. KH and TW performed H&E and IHC experiments. SOT independently assessed and scored all histology in this study. GA-E interpreted and performed analyses of immune cells with intellectual input from SJ. C-AD and FG provided intellectual input related to myeloid cluster annotation. SZW interpreted and performed all analyses of stromal cells. DK and CL-C performed Visium experiments with input from JEP. VG helped perform pre-processing of Visium datasets. SRW, NIW, CRU, JGC and ZWB performed Visium experiments and data processing from an independent laboratory. AA performed the Stereoscope deconvolution with input from JL. SZW performed downstream analysis of Visium data with guidance from AA, LL, GA-E and JL. DR interpreted and performed CIBERSORTx analysis. SZW and DR performed survival analyses. CW and XSL provided intellectual input and guidance on bulk deconvolution and survival analyses. Author Contributions These authors contributed equally
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-00911-1