单细胞 RNA 测序数据集的生物信息学分析揭示了三阴性乳腺癌在转录谱、剪接事件和串扰网络中的细胞异质性。

Bioinformatic analysis of single-cell RNA sequencing dataset dissects cellular heterogeneity of triple-negative breast cancer in transcriptional profile, splicing event and crosstalk network.

机构信息

Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, China.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.

出版信息

Clin Transl Oncol. 2023 Jun;25(6):1856-1868. doi: 10.1007/s12094-023-03083-y. Epub 2023 Jan 24.

DOI:10.1007/s12094-023-03083-y

PMID:36692641

Abstract

BACKGROUND

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high tumoral heterogeneity, while the detailed regulatory network is not well known.

METHODS

Via single-cell RNA-sequencing (scRNA-seq) data analysis, we comprehensively investigated the transcriptional profile of different subtypes of TNBC epithelial cells with gene regulatory network (GRN) and alternative splicing (AS) event analysis, as well as the crosstalk between epithelial and non-epithelial cells.

RESULTS

Of note, we found that luminal progenitor subtype exhibited the most complex GRN and splicing events. Besides, hnRNPs negatively regulates AS events in luminal progenitor subtype. In addition, we explored the cellular crosstalk among endothelial cells, stromal cells and immune cells in TNBC and discovered that NOTCH4 was a key receptor and prognostic marker in endothelial cells, which provide potential biomarker and target for TNBC intervention.

CONCLUSIONS

In summary, our study elaborates on the cellular heterogeneity of TNBC, revealing that NOTCH4 in endothelial cells was critical for TNBC intervention. This in-depth understanding of epithelial cell and non-epithelial cell network would provide theoretical basis for the development of new drugs targeting this sophisticated network in TNBC.

摘要

背景

三阴性乳腺癌（TNBC）是一种具有高肿瘤异质性的乳腺癌亚型，但其详细的调控网络尚不清楚。

方法

通过单细胞 RNA 测序（scRNA-seq）数据分析，我们全面研究了不同亚型 TNBC 上皮细胞的转录谱，包括基因调控网络（GRN）和选择性剪接（AS）事件分析，以及上皮细胞和非上皮细胞之间的相互作用。

结果

值得注意的是，我们发现腔前体细胞亚型表现出最复杂的 GRN 和剪接事件。此外，hnRNPs 负调控腔前体细胞亚型中的 AS 事件。此外，我们还探索了 TNBC 中内皮细胞、基质细胞和免疫细胞之间的细胞串扰，并发现 NOTCH4 是内皮细胞中的关键受体和预后标志物，为 TNBC 的干预提供了潜在的生物标志物和靶点。