{"doi":"10.1186/s13073-024-01407-3","title":"Integrated single-cell analysis reveals distinct epigenetic-regulated cancer cell states and a heterogeneity-guided core signature in tamoxifen-resistant breast cancer","abstract":"BACKGROUND: Inter- and intra-tumor heterogeneity is considered a significant factor contributing to the development of endocrine resistance in breast cancer. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) allow us to explore inter- and intra-tumor heterogeneity at single-cell resolution. However, such integrated single-cell analysis has not yet been demonstrated to characterize the transcriptome and chromatin accessibility in breast cancer endocrine resistance. METHODS: In this study, we conducted an integrated analysis combining scRNA-seq and scATAC-seq on more than 80,000 breast tissue cells from two normal tissues (NTs), three primary tumors (PTs), and three tamoxifen-treated recurrent tumors (RTs). A variety of cell types among breast tumor tissues were identified, PT- and RT-specific cancer cell states (CSs) were defined, and a heterogeneity-guided core signature (HCS) was derived through such integrated analysis. Functional experiments were performed to validate the oncogenic role of BMP7, a key gene within the core signature. RESULTS: We observed a striking level of cell-to-cell heterogeneity among six tumor tissues and delineated the primary to recurrent tumor progression, underscoring the significance of these single-cell level tumor cell clusters classified from scRNA-seq data. We defined nine CSs, including five PT-specific, three RT-specific, and one PT-RT-shared CSs, and identified distinct open chromatin regions of CSs, as well as a HCS of 137 genes. In addition, we predicted specific transcription factors (TFs) associated with the core signature and novel biological/metabolism pathways that mediate the communications between CSs and the tumor microenvironment (TME). We finally demonstrated that BMP7 plays an oncogenic role in tamoxifen-resistant breast cancer cells through modulating MAPK signaling pathways. CONCLUSIONS: Our integrated single-cell analysis provides a comprehensive understanding of the tumor heterogeneity in tamoxifen resistance. We envision this integrated single-cell epigenomic and transcriptomic measure will become a powerful approach to unravel how epigenetic factors and the tumor microenvironment govern the development of tumor heterogeneity and to uncover potential therapeutic targets that circumvent heterogeneity-related failures.","journal":"Genome Medicine","year":2024,"id":421733,"datarank":0.6775430385516811,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.16736343130235765,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.16736343130235765,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":27,"citers_with_citation_signal":13,"citers_with_endowment":13,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.932,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE240112"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1215235,"name":"Aigbe G. Ohihoin","orcid":null,"position":1,"is_corresponding":false},{"id":1214695,"name":"Tianxiang Liu","orcid":"0000-0001-5344-1203","position":2,"is_corresponding":false},{"id":504175,"name":"Lavanya Choppavarapu","orcid":null,"position":3,"is_corresponding":false},{"id":378168,"name":"Bakhtiyor Nosirov","orcid":"0000-0002-4644-2758","position":4,"is_corresponding":false},{"id":291660,"name":"Qianben Wang","orcid":"0000-0003-2636-7145","position":5,"is_corresponding":false},{"id":321624,"name":"Xue‐Zhong Yu","orcid":"0000-0002-1751-2884","position":6,"is_corresponding":false},{"id":513677,"name":"Sailaja Kamaraju","orcid":"0000-0003-3031-9269","position":7,"is_corresponding":false},{"id":316405,"name":"Gustavo Leone","orcid":"0000-0002-7617-7449","position":8,"is_corresponding":false},{"id":88614,"name":"Victor X. Jin","orcid":"0000-0002-8765-3471","position":9,"is_corresponding":false},{"id":503627,"name":"Kun Fang","orcid":"0000-0002-2569-8543","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T01:57:41.370244Z","pmid":"39558215","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}