TREM2+ Macrophage Infiltration Underlies Breast Cancer Lung Metastasis due to Paclitaxel Treatment [ATAC-seq]
Metastasis is a major cause of breast-cancer-related death and frequently occurs following paclitaxel neoadjuvant chemotherapy failure. Tumor microenvironment contributes to metastasis, while the role of specific host cells in lung metastases induced by paclitaxel (PTX) treatment remains poorly understood. Here, we demonstrate that PTX neoadjuvant chemotherapy promotes triggering receptor expressed on myeloid cells-2 (TREM2)-positive macrophage infiltration in the breast cancer tissues of patients. Meanwhile, we also show that more TREM2-positive macrophage infiltrates in breast cancer tissues of patients with lung -metastasized. Genetic TREM2 deficiency decreases breast cancer lung metastases induced by PTX treatment in vivo, suggesting that TREM2-positive macrophages are essential for PTX-promoting lung metastasis of breast cancer. We further reveal that PTX promotes tumor cell secretion of fibroblast growth factor 2 (FGF2), triggering TREM2 transcription via upregulating its transcriptional factor early growth response-1 (EGR1) in macrophages. Increased TREM2 activates epithelial-mesenchymal transition (EMT)-related cytokine secretion in macrophages, inducing tumor cell lung metastases. Targeting TREM2 significantly suppressed lung metastasis in breast-cancer-bearing mice. Our findings establish that tumor-cell-derived FGF2 induced by paclitaxel treatment upregulates TREM2 in myeloid macrophages, which in turn promotes the EMT of neighboring tumor cells through cytokine secretion. Our results highlight TREM2 as a potential therapeutic target to mitigate lung metastasis due to PTX treatment. Overall design: ATAC-seq of BT549-D, BT549-P, BT549-PB, BT549-NP, BMDM-D, BMDM-P, BMDM-PB, BMDM-NP were harvested and analyzed