共生巨噬细胞-神经胶质瘤细胞相互作用揭示了 PTEN 缺失型神经胶质瘤的合成致死性。
Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma.
机构信息
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
出版信息
Cancer Cell. 2019 Jun 10;35(6):868-884.e6. doi: 10.1016/j.ccell.2019.05.003.
Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.
不同细胞类型之间的异型相互作用能够促进肿瘤进展，并有可能扩大治疗干预的范围。在这里，通过对胶质母细胞瘤 (GBM) 模型中的神经胶质瘤细胞进行联合分析和功能研究，确定了 PTEN 缺失会激活 YAP1，而 YAP1 可直接上调赖氨酰氧化酶 (LOX) 的表达。从机制上讲，分泌的 LOX 通过激活巨噬细胞中的β1 整合素-PYK2 途径，充当巨噬细胞的强效趋化因子。这些浸润的巨噬细胞分泌 SPP1，维持神经胶质瘤细胞的存活并刺激血管生成。在 PTEN 缺失的 GBM 模型中，LOX 抑制显著抑制巨噬细胞浸润和肿瘤进展。相应地，YAP1-LOX 和β1 整合素-SPP1 信号与 GBM 患者中更高的巨噬细胞密度和更低的总体生存率呈正相关。这种共生的神经胶质瘤-巨噬细胞相互作用为 PTEN 缺失型 GBM 提供了特定的治疗靶点。
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