Deciphering the Immune Microenvironment at the Forefront of Tumor Aggressiveness by Constructing a Regulatory Network with Single-Cell and Spatial Transcriptomic Data

Author:

Xu Kun12,Yu Dongshuo2,Zhang Siwen2,Chen Lanming3,Liu Zhenhao2ORCID,Xie Lu12ORCID

Affiliation:

1. College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China

2. Shanghai-MOST Key Laboratory of Health and Disease Genomics, The Institute of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200037, China

3. Key Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation (Shanghai), China Ministry of Agriculture, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China

Abstract

The heterogeneity and intricate cellular architecture of complex cellular ecosystems play a crucial role in the progression and therapeutic response of cancer. Understanding the regulatory relationships of malignant cells at the invasive front of the tumor microenvironment (TME) is important to explore the heterogeneity of the TME and its role in disease progression. In this study, we inferred malignant cells at the invasion front by analyzing single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data of ER-positive (ER+) breast cancer patients. In addition, we developed a software pipeline for constructing intercellular gene regulatory networks (IGRNs), which help to reduce errors generated by single-cell communication analysis and increase the confidence of selected cell communication signals. Based on the constructed IGRN between malignant cells at the invasive front of the TME and the immune cells of ER+ breast cancer patients, we found that a high expression of the transcription factors FOXA1 and EZH2 played a key role in driving tumor progression. Meanwhile, elevated levels of their downstream target genes (ESR1 and CDKN1A) were associated with poor prognosis of breast cancer patients. This study demonstrates a bioinformatics workflow of combining scRNA-seq and ST data; in addition, the study provides the software pipelines for constructing IGRNs automatically (cIGRN). This strategy will help decipher cancer progression by revealing bidirectional signaling between invasive frontline malignant tumor cells and immune cells, and the selected signaling molecules in the regulatory network may serve as biomarkers for mechanism studies or therapeutic targets.

Funder

National Natural Science Foundation of China

Shanghai Municipal Health Commission, and Collaborative Innovation Cluster Project

Publisher

MDPI AG

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