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TREM2+ Macrophage Infiltration Underlies Breast Cancer Lung Metastasis due to Paclitaxel Treatment

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285485 | GEO | 2025/11/16

REPOSITORIES: GEO

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Project description:Gene Expression Profiling of Breast Cancer Patients with Brain Metastases Brain metastases confer the worst prognosis of breast cancer as no therapy exists that prevents or eliminates the cancer from spreading to the brain. We developed a new computational modeling method to derive specific downstream signaling pathways that reveal unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available gene expression data of patients. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed the specific CSBs for each metastasis that satisfy that (1) CSB proteins are activated by the maximal number of enriched signaling pathways specific to this metastasis, and (2) CSB proteins involve in the most differential expressed coding-genes specific to the specific breast cancer metastasis. The identified signaling networks for the three types of metastases contain 31, 15, and 18 proteins, respectively, and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases of breast cancer. We performed in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Two known drugs, Sunitinib (FDA approved for renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor) and Dasatinib (FDA approved for chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia), were shown to prohibit the metastatic colonization in brain. The TMH-52 cohort includes 11 patients who were examined with brain metastasis at the time of breast cancer diagnosis. The other 41 patients were examined with other organ metastasis at the time of breast cancer diagnosis.

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TREM2+ Macrophage Infiltration Underlies Breast Cancer Lung Metastasis due to Paclitaxel Treatment

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