文章：

转移微环境中的异质性：表达JunB的小胶质细胞作为黑色素瘤脑转移进展的潜在驱动因素

Heterogeneity in the Metastatic Microenvironment: JunB-Expressing Microglia Cells as Potential Drivers of Melanoma Brain Metastasis Progression

原文发布日期：13 October 2023

DOI: 10.3390/cancers15204979

类型: Article

开放获取: 是

英文摘要：

Reciprocal signaling between melanoma brain metastatic (MBM) cells and microglia reprograms the phenotype of both interaction partners, including upregulation of the transcription factor JunB in microglia. Here, we aimed to elucidate the impact of microglial JunB upregulation on MBM progression. For molecular profiling, we employed RNA-seq and reverse-phase protein array (RPPA). To test microglial JunB functions, we generated microglia variants stably overexpressing JunB (JunBhi) or with downregulated levels of JunB (JunBlo). Melanoma-derived factors, namely leukemia inhibitory factor (LIF), controlled JunB upregulation through Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling. The expression levels of JunB in melanoma-associated microglia were heterogeneous. Flow cytometry analysis revealed the existence of basal-level JunB-expressing microglia alongside microglia highly expressing JunB. Proteomic profiling revealed a differential protein expression in JunBhiand JunBlocells, namely the expression of microglia activation markers Iba-1 and CD150, and the immunosuppressive molecules SOCS3 and PD-L1. Functionally, JunBhimicroglia displayed decreased migratory capacity and phagocytic activity. JunBlomicroglia reduced melanoma proliferation and migration, while JunBhimicroglia preserved the ability of melanoma cells to proliferate in three-dimensional co-cultures, that was abrogated by targeting leukemia inhibitory factor receptor (LIFR) in control microglia–melanoma spheroids. Altogether, these data highlight a melanoma-mediated heterogenous effect on microglial JunB expression, dictating the nature of their functional involvement in MBM progression. Targeting microglia highly expressing JunB may potentially be utilized for MBM theranostics.

摘要翻译： 

黑色素瘤脑转移（MBM）细胞与小胶质细胞之间的双向信号传导重塑了相互作用双方的表型，包括小胶质细胞中转录因子JunB的上调。本研究旨在阐明小胶质细胞JunB上调对MBM进展的影响。我们采用RNA测序和反相蛋白阵列进行分子谱分析。为验证小胶质细胞JunB功能，构建了稳定过表达JunB（JunB高表达型）及JunB表达下调（JunB低表达型）的小胶质细胞变体。黑色素瘤来源因子——白血病抑制因子（LIF）通过Janus激酶（JAK）/信号转导与转录激活因子3（STAT3）信号通路调控JunB上调。黑色素瘤相关小胶质细胞中JunB表达水平呈现异质性，流式细胞术分析显示存在基础水平表达JunB的小胶质细胞与高表达JunB的小胶质细胞亚群。蛋白质组学分析揭示JunB高表达与低表达细胞存在差异蛋白表达，包括小胶质细胞活化标志物Iba-1和CD150，以及免疫抑制分子SOCS3和PD-L1。功能实验表明：JunB高表达型小胶质细胞迁移能力和吞噬活性降低；JunB低表达型小胶质细胞可抑制黑色素瘤增殖与迁移，而JunB高表达型小胶质细胞在三维共培养体系中维持黑色素瘤细胞增殖能力——该效应可通过靶向对照组小胶质细胞-黑色素瘤球体中的白血病抑制因子受体（LIFR）而消除。综上，这些数据揭示了黑色素瘤对小胶质细胞JunB表达的异质性调控作用，决定了其在MBM进展中的功能参与特性。靶向高表达JunB的小胶质细胞可能为MBM诊疗提供新策略。

原文链接：

Heterogeneity in the Metastatic Microenvironment: JunB-Expressing Microglia Cells as Potential Drivers of Melanoma Brain Metastasis Progression