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Immature Low-Density Neutrophils Exhibit Metabolic Flexibility that Facilitates Breast Cancer Liver Metastasis.
Cell Reports ( IF 7.5 ) Pub Date : 2019-06-25 , DOI: 10.1016/j.celrep.2019.05.091
Brian E Hsu 1 , Sébastien Tabariès 2 , Radia M Johnson 3 , Sylvia Andrzejewski 2 , Julien Senecal 1 , Camille Lehuédé 2 , Matthew G Annis 2 , Eric H Ma 4 , Sandra Völs 5 , LeeAnn Ramsay 2 , Remi Froment 6 , Anie Monast 2 , Ian R Watson 2 , Zvi Granot 5 , Russell G Jones 4 , Julie St-Pierre 7 , Peter M Siegel 1
Affiliation  

Neutrophils are phenotypically heterogeneous and exert either anti- or pro-metastatic functions. We show that cancer-cell-derived G-CSF is necessary, but not sufficient, to mobilize immature low-density neutrophils (iLDNs) that promote liver metastasis. In contrast, mature high-density neutrophils inhibit the formation of liver metastases. Transcriptomic and metabolomic analyses of high- and low-density neutrophils reveal engagement of numerous metabolic pathways specifically in low-density neutrophils. iLDNs exhibit enhanced global bioenergetic capacity, through their ability to engage mitochondrial-dependent ATP production, and remain capable of executing pro-metastatic neutrophil functions, including NETosis, under nutrient-deprived conditions. We demonstrate that NETosis is an important neutrophil function that promotes breast cancer liver metastasis. iLDNs rely on the catabolism of glutamate and proline to support mitochondrial-dependent metabolism in the absence of glucose, which enables sustained NETosis. These data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates the formation of liver metastases.



中文翻译:

不成熟的低密度中性粒细胞表现出促进乳腺癌肝转移的代谢灵活性。

中性粒细胞在表型上是异质的,并发挥抗转移或促转移功能。我们显示癌细胞来源的G-CSF是必要的,但不足以动员未成熟的低密度中性粒细胞(iLDNs),以促进肝转移。相反,成熟的高密度中性粒细胞抑制肝转移的形成。高密度和低密度嗜中性粒细胞的转录组学和代谢组学分析揭示了许多代谢途径,特别是低密度嗜中性粒细胞的参与。iLDN通过参与线粒体依赖性ATP产生的能力表现出增强的全球生物能能力,并且在营养剥夺的条件下仍然能够执行促转移性中性粒细胞功能,包括NETosis。我们证明NETosis是一种重要的中性粒细胞功能,可促进乳腺癌肝转移。iLDNs在没有葡萄糖的情况下依赖谷氨酸和脯氨酸的分解代谢来支持线粒体依赖性代谢,从而实现持续的NETosis。这些数据表明,不同的促转移中性粒细胞群体表现出高度的代谢灵活性,从而促进了肝转移瘤的形成。

更新日期:2019-06-25
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