CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
Nat Commun. 2022 Feb 16;13(1):897. doi: 10.1038/s41467-022-28438-x.
The formation of pre-metastatic niche is a key step in the metastatic burden. The pluripotent factor Lin28B is frequently expressed in breast tumors and is particularly upregulated in the triple negative breast cancer subtype. Here, we demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. Lin28B enables neutrophil recruitment and N2 conversion. The N2 neutrophils are then essential for immune suppression in pre-metastatic lung by PD-L2 up-regulation and a dysregulated cytokine milieu. We also identify that breast cancer-released exosomes with low let-7s are a prerequisite for Lin28B-induced immune suppression. Moreover, Lin28B-induced breast cancer stem cells are the main sources of low-let-7s exosomes. Clinical data further verify that high Lin28B and low let-7s in tumors are both indicators for poor prognosis and lung metastasis in breast cancer patients. Together, these data reveal a mechanism by which Lin28B directs the formation of an immune-suppressive pre-metastatic niche.
前转移龛的形成是转移负担的关键步骤。多能因子 Lin28B 在乳腺癌中经常表达，并且在三阴性乳腺癌亚型中特别上调。在这里，我们证明 Lin28B 通过构建免疫抑制性前转移龛促进乳腺癌的肺转移。Lin28B 能够招募中性粒细胞并促进 N2 转化。N2 中性粒细胞对于前转移肺中的免疫抑制是必不可少的，通过 PD-L2 的上调和细胞因子环境的失调来实现。我们还发现，乳腺癌释放的低 let-7 的外泌体是 Lin28B 诱导免疫抑制的先决条件。此外，Lin28B 诱导的乳腺癌干细胞是低 let-7 的外泌体的主要来源。临床数据进一步证实，肿瘤中高 Lin28B 和低 let-7s 都是乳腺癌患者预后不良和肺转移的指标。总之，这些数据揭示了 Lin28B 指导免疫抑制性前转移龛形成的机制。
