Goodman Cancer Research Centre, McGill University, Montreal, Québec, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montreal, Québec, QC H3G 1Y6, Canada.
Goodman Cancer Research Centre, McGill University, Montreal, Québec, QC H3A 1A3, Canada.
Cell Rep. 2019 Jun 25;27(13):3902-3915.e6. doi: 10.1016/j.celrep.2019.05.091.
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.
中性粒细胞在表型上具有异质性，并发挥抗转移或促转移功能。我们发现，癌细胞衍生的 G-CSF 对于动员促进肝转移的不成熟低密中性粒细胞（iLDNs）是必需的，但不是充分的。相比之下，成熟的高密中性粒细胞则抑制肝转移的形成。高密和低密中性粒细胞的转录组和代谢组分析揭示了许多代谢途径在低密中性粒细胞中特异性参与。iLDNs 通过其能够进行依赖线粒体的 ATP 产生来增强整体生物能量能力，并且在营养缺乏条件下仍然能够发挥促转移中性粒细胞功能，包括 NETosis。我们证明 NETosis 是促进乳腺癌肝转移的重要中性粒细胞功能。iLDNs 依赖于谷氨酸和脯氨酸的分解代谢来支持葡萄糖缺乏时依赖线粒体的代谢，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，这有利于肝转移的形成。
