Differential Adaptation and Remodeling of the Tumor Microenvironment in Breast Cancer Cells During the Stages of Brain Metastasis

Objective To integrate macro-transcriptomics and single-cell sequencing to analyze the differential gene expression between primary and brain metastatic breast cancer cells, as well as between active and dormant cancer cells within brain metastases, exploring their adaptation and remodeling abilities at different stages of brain metastasis. Methods Four public datasets were used: three mRNA microarray datasets from breast cancer and brain metastasis tissues, and one single-cell RNA sequencing (scRNA-seq) dataset from active and dormant brain metastatic cells. Gene differential expression, pathway enrichment, and cell clustering analyses were performed to compare primary and metastatic breast cancer cells, as well as active and dormant cells in brain metastases, focusing on gene expression, metabolic pathways, and functional pathways. Results Metastatic breast cancer cells showed weakened pathways related to the extracellular matrix and protein digestion. Active cells exhibited enhanced cell cycle regulation, tumor proliferation, and hypoxia resistance pathways compared to dormant cells. Clustering analysis revealed that cluster 6, unique to dormant cells, had enhanced functions in epithelial-mesenchymal transition (EMT), extracellular matrix (ECM), collagen formation, tumor inflammation siganure (TIS), and IL-10 signaling. Cluster 3 and 4 in active cells had enhanced DNA replication and tumor proliferation pathways, respectively. Conclusion This study highlights the role of cancer cell characteristics and heterogeneity in the invasiveness of brain metastasis. Understanding these mechanisms can guide the development of more effective treatment strategies for breast cancer brain metastasis (BCBM) patients.