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Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis
Yu Jin1, Yalin Kang1, Minghuan Wang2
1Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
Abstract:
Tumor-associated macrophages have emerged as crucial factors for metastases. Microglia are indispensable components of the brain microenvironment and play vital roles in brain metastasis (BM). However, the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) remains elusive. Here, we purified cell lines with brain-metastatic tropism and employed a co-culture system to reveal their communication with microglia. By single-cell RNA-sequencing and transcriptome difference analysis, we identified IL6 as the key regulator in brain-metastatic cells (A549-F3) to induce anti-inflammatory microglia via JAK2/STAT3 signaling, which in turn promoted the colonization process in metastatic A549-F3 cells. In our clinical samples, patients with higher levels of IL6 in serum showed higher propensity for brain metastasis. Additionally, the TCGA (The Cancer Genome Atlas) data revealed that NSCLC patients with a lower level of IL6 had a longer overall survival time compared to those with a higher level of IL6. Overall, our data indicate that the targeting of IL6/JAK2/STAT3 signaling in activated microglia may be a promising new approach for inhibiting brain metastasis in NSCLC patients.
Insights
Interleukin-6 (IL6) produced by non-small cell lung cancer (NSCLC) cells activates microglia, promoting brain metastasis. Targeting the IL6/JAK2/STAT3 pathway may inhibit NSCLC brain metastasis.
Area of Science:
- Neuro-oncology
- Cancer biology
- Immunology
Background:
- Tumor-associated macrophages, including microglia in the brain, are implicated in cancer metastasis.
- The precise mechanisms by which microglia promote non-small cell lung cancer (NSCLC) brain metastasis are not fully understood.
Purpose of the Study:
- To elucidate the communication between brain-metastatic NSCLC cells and microglia.
- To identify key molecular regulators driving NSCLC brain metastasis.
Main Methods:
- Co-culture system of brain-metastatic NSCLC cells (A549-F3) and microglia.
- Single-cell RNA-sequencing and transcriptome analysis.
- Analysis of clinical samples and The Cancer Genome Atlas (TCGA) data.
Main Results:
- IL6 was identified as a key mediator secreted by metastatic NSCLC cells.
- IL6 induced an anti-inflammatory phenotype in microglia via the JAK2/STAT3 signaling pathway.
- This microglial activation promoted NSCLC cell colonization in the brain.
- Higher serum IL6 levels correlated with increased brain metastasis in patients.
- Lower IL6 levels in NSCLC patients were associated with longer overall survival.
Conclusions:
- The IL6/JAK2/STAT3 signaling axis in microglia plays a critical role in promoting NSCLC brain metastasis.
- Targeting this pathway presents a potential therapeutic strategy for inhibiting brain metastasis in NSCLC.
