Revealing Cellular Heterogeneity and Key Regulatory Factors of Triple-Negative Breast Cancer through Single-Cell RNA Sequencing.

Autor:	Zhang H; School of Basic Medical Sciences, Jiangsu Vocational College of Medicine, 224005 Yancheng, Jiangsu, China., Sun Y; Department of General Surgery, Research Unit of General Surgery, Beijing Yanging Hospital of Traditional Chinese Medicine, 102100 Beijing, China., Du X; School of Basic Medical Sciences, Jiangsu Vocational College of Medicine, 224005 Yancheng, Jiangsu, China.
Jazyk:	angličtina
Zdroj:	Frontiers in bioscience (Landmark edition) [Front Biosci (Landmark Ed)] 2024 Aug 19; Vol. 29 (8), pp. 290.
DOI:	10.31083/j.fbl2908290
Abstrakt:	Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC). TNBC has a poor prognosis due to high intratumoral heterogeneity and metastasis, pointing to the need to explore distinct molecular subtypes and gene regulatory networks. Methods: The scRNA-seq data of five primary BC samples were downloaded from the Gene Expression Omnibus (GEO) database. Clustering was performed based on filtered and normalized data using the Seurat R package to identify marker genes, which were subsequently annotated to each subset using the CellMarker database. AUCell R package was applied to calculate the hallmark score for each epithelial cell. Marker genes of each subset were screened with FindAllMarkers and their biological functions were analyzed using the Database for Annotation Visualization and Integrated Discovery (DAVID) database. Next, cell-cell communication was performed with the CellChat R package. To identify the key regulatory genes, single-cell regulatory network inference and clustering (SCENIC) analysis was conducted. Finally, the expression and potential biological functions of the key regulatory factors were verified through cellular experiments. Results: A total of 29,101 cells were classified into nine cell subsets, namely, Fibroblasts, Fibroepithelial cells, Epithelial cells 1, Epithelial cells 2, Epithelial cells 3, Endothelial cells, T cells, Plasma B cells and Macrophages. Particularly, the epithelial cells had a higher proportion and higher transforming growth factor-β (TGF-β) activity in the TNBC pathotype as compared to the non-TNBC pathotype. Furthermore, four epithelial cell subsets (marked as Stearoyl-CoA Desaturase ( SCD1 ), marker of proliferation Ki67 ( MKI67 ), Annexin A3 ( ANXA3 ) and aquaporin 5 ( AQP5 )) were identified as having the greatest impact on the TNBC pathotype. Cell-cell interaction analysis revealed that ANXA3-epithelial cell subset suppressed the T cell function through different mechanisms. C-fos gene ( FOS ) and X-box binding protein 1 ( XBP1 ) were considered critical regulons involved in TNBC progression. Notably, cellular experiments demonstrated that silencing XBP1 and overexpressing FOS inhibited cancer cell invasion. Conclusion: The four epithelial cell subsets and two critical regulons identified based on the scRNA-seq data could help explore the underlying intratumoral heterogeneity molecular mechanism and develop effective therapies for TNBC. Competing Interests: The authors declare no conflict of interest. (© 2024 The Author(s). Published by IMR Press.)
Databáze:	MEDLINE
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