Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis
Summary
The crucial role of tumor-associated macrophages in metastases is now well-established. In particular, microglia have been found to play an essential role in brain metastasis (BM) by shaping the brain microenvironment. However, the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) is still not clear. Researchers utilized a co-culture system to study the communication between brain-metastatic tropism cell lines and microglia. Through single-cell RNA-sequencing and transcriptome difference analysis, they identified IL6 as the key regulator in brain-metastatic cells that induces anti-inflammatory microglia via JAK2/STAT3 signaling. This, in turn, promotes the colonization process in metastatic cells. Clinical data also suggests that targeting IL6/JAK2/STAT3 signaling in activated microglia may be a promising approach to inhibit brain metastasis in NSCLC patients.
Research Criteria
The research idea of this article is to investigate the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) and identify therapeutic targets for preventive treatment in NSCLC-BM.
Fig.1 Experimental design. (Jin, 2022)
Sample Type
Cells from mouse brain.
Result—Single-Cell RNA-Seq Revealed Activated Microglia in A549 Cell BM
In an endeavor to expound upon the potential mechanisms governing cellular communication between non-small cell lung cancer brain metastasis (NSCLC BM) cells and activated microglia, researchers conducted a series of in vivo and in vitro experiments. They acquired highly brain-metastatic NSCLC cells through inoculating A549 cells into the left cardiac ventricles of mice, which were subjected to successive rounds of in vivo selection. The metastatic activity of these cells, including A549-F1, A549-F2, and A549-F3, was confirmed through bioluminescence imaging and histological analysis. Malignant phenotypes of various cell lines were assessed, revealing enhanced invasiveness and migration activities in derivative cells compared to parent A549-F0 cells. Subsequently, single-cell RNA-seq was employed to sort microglia and analyze the differences in cell clusters between metastatic and healthy groups. Researchers identified 20 cell clusters, with the majority being microglia, and observed an overlap between metastatic lesions from A549 and A549-F3 cells. Furthermore, anti-inflammatory microglia were found to be dominant in both A549 and A549-F3 groups, while the control group exhibited an equilibrium state between anti-inflammatory and pro-inflammatory microglia. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed upregulation of the JAK/STAT pathway, which is known to be implicated in tumor-associated macrophage (TAM) activation, corroborating the presence of M2 microglia in NSCLC-BM in vivo.
Fig.2 Single-cell RNA-seq reveals activated microglia in metastatic lesions. (Jin, 2022)
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Reference
- Jin, Y.; et al. Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis. Signal Transduction and Targeted Therapy. 2022, 7(1): 1-12.
