ORIGINAL RESEARCH article
Front. Genet.
Sec. Computational Genomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1614254
Multi-omics integration uncovers key transcriptional regulators in triple-negative breast cancer spatial heterogeneity
Provisionally accepted
Ning Zhang1*
Ye Zhang1Rui-Fei Yang1Hai-Qing Chu1
Dong Zhao1Luyu Yang2Yayu Li3
Abdur Rehman2
XIN ZHOU1Shou-Ping Gong1
Hui-Ling Cao1- 1Xi'an Medical University, Xi'an, China
- 2Northwest A & F University Hospital, xianyang, China
- 3Northwest A&F University, Xianyang, Shaanxi Province, China
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Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a lack of hormone receptors, making it challenging to treat.We generated a comprehensive spatial cell atlas of TNBC using a multiomics integration approach that combined single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics. This integration allowed us to characterize the spatial microenvironment and map the cell-type-specific distributions in TNBC tissues.Results: Our analysis revealed significant heterogeneity in cell types and spatial distribution, with normal regions enriched in insulin resistance functions, whereas cancerous regions displayed diverse cell populations, including immune cells, cancerassociated fibroblasts (CAFs), and mesenchymal cells. By constructing transcription factor (TF) regulatory networks, we identified TFF3, RARG, GRHL1, RORC, and KLF5 as critical regulators of epithelial cells, whereas EMX2, TWIST1, TWIST2, NFATC4, and HOXC6 were found to play essential roles in mesenchymal cells.Immunohistochemical validation supported the involvement of these TFs in TNBC.Further analysis of receptor-ligand interactions highlighted the roles of KNG1_BDKRB2 and NRG1_ERBB4 signaling in promoting tumor aggression, suggesting potential therapeutic targets. GO enrichment analysis revealed overlapping pathways between epithelial and mesenchymal cells, focusing on migration, signaling, and development, indicating that the shared regulatory mechanisms contribute to cancer progression.Our findings provide new insights into the TNBC microenvironment, emphasizing the complex spatial interactions between different cell types and highlighting key regulatory pathways that could be targeted for future therapeutic interventions. This spatial cell atlas lays the foundation for further exploration of tumor microenvironment dynamics and precision oncology approaches.
Keywords: Triple-negative breast cancer, Spatial transcriptomics, microenvironment, tumor spread, Cell heterogeneity
Received: 18 Apr 2025; Accepted: 14 Aug 2025.
Copyright: © 2025 Zhang, Zhang, Yang, Chu, Zhao, Yang, Li, Rehman, ZHOU, Gong and Cao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ning Zhang, Xi'an Medical University, Xi'an, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.