Single-cell RNA-seq dissects the intratumoral heterogeneity of triple-negative breast cancer based on gene regulatory networks

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high intratumoral heterogeneity. Recent studies re-vealed that TNBC patients might comprise cells with distinct molecular subtypes. In addition, gene regulatory networks (GRNs) constructed based on single-cell RNA sequencing (scRNA-seq) data have demonstrated the significance for de-coding the key regulators. We performed a comprehensive analysis of the GRNs for the intrinsic subtypes of TNBC pa-tients using scRNA-seq. The copy number variations (CNVs) were inferred from scRNA-seq data and identified 545 malig-nant cells. The subtypes of the malignant cells were assigned based on the PAM50 model. The cell-cell communication anal-ysis revealed that the macrophage plays a dominant role in the tumor microenvironment. Next, the GRN for each subtype was constructed through integrating gene co-expression and enrichment of transcription-binding motifs. Then, we identi-fied the critical genes based on the centrality metrics of genes. Importantly, the critical gene ETV6 was ubiquitously upregu-lated in all subtypes, but it exerted diverse roles in each subtype through regulating different target genes. In conclusion, the construction of GRNs based on scRNA-seq data could help us to dissect the intratumoral heterogeneity and identify the crit-ical genes of TNBC.

Automated summary

A comprehensive analysis of gene regulatory networks for intrinsic subtypes of TNBC patients was conducted, revealing different subtypes of malignant cells and the dominant role of macrophages in the tumor microenvironment. The critical gene ETV6 was found to be universally upregulated in all subtypes and exerted diverse roles in each subtype.