Integration analysis of single-cell transcriptome reveals SPP1+ and TFF3+ macrophage subsets contributing to the brain metastasis from lung cancer.

Background: The death of lung cancer patients is closely linked to brain metastasis. While tumor-associated macrophages (TAMs) have been extensively studied in the context of lung cancer metastasis, their role and mechanism in brain metastasis remain unclear. In this study, we analyzed and explored the heterogeneity and differential gene expression of TAM subsets associated with brain metastasis of lung cancer using single-cell transcriptome data. Methods: Single-cell RNA sequencing datasets related to brain metastasis of lung cancer were acquired from the Gene Expression Omnibus (GEO) database and ArrayExpress platform. Through standard single-cell data analysis and visualization, we investigated the differential gene expression and signal pathway enrichment of macrophage subsets associated with brain metastasis of lung cancer, focusing on the unique microenvironment and cell component differences in brain metastasis tissues. Results: Compared with normal lung tissue, brain tissue, and tumor focus of primary lung cancer, we observed a significant up-regulation in the cell proportions of SPP1+ macrophages and TFF3+ macrophages in brain metastasis tissues of lung cancer. These macrophage subsets up-regulated various factors promoting tumor progression and metastasis. SPP1+ macrophages significantly up-regulated the expressions of SPP1, CCL2, MIF, and AREG, while TFF3+ macrophages up-regulated the expressions of TFF3, TFF1, CCL4, CCL3, AGR2, CCL3L3, and CCL4L2. Signal pathway analysis revealed obvious enrichment in the NOD-like receptor signaling pathway, Chemokine signaling pathway, NF-kappa B signaling pathway, and TNF signaling pathway in these two macrophage subsets. Conclusions: Our findings demonstrate the close association of SPP1+ and TFF3+ macrophage subsets with brain metastasis of lung cancer. Our differential gene and signaling pathway analysis revealed the potential tumor-promoting mechanisms. These insights may offer new perspectives for clinical strategies targeting macrophages or the tumor microenvironment to treat brain metastasis of lung cancer.