The Third Affiliated Hospital of Soochow University/The First People's Hospital of Changzhou, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine of Soochow University, Suzhou, Jiangsu, China.
Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Center, Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
Nat Commun. 2021 Oct 27;12(1):6202. doi: 10.1038/s41467-021-26460-z.
Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.
转移前生态位形成对于播散的癌细胞在远处器官的定植至关重要。在这里，我们发现转移前阶段的肺间质基质细胞（LMSC）具有很强的促进转移的活性。RNA-seq 显示，这些 LMSC 中补体 3（C3）的表达上调。发现 C3 可促进中性粒细胞募集和中性粒细胞胞外诱捕网（NETs）的形成，从而促进癌细胞转移到肺部。LMSC 中 C3 的表达通过 STAT6 依赖的方式被 Th2 细胞因子诱导和维持。在 Th1 偏向 Stat6 缺陷型小鼠中，LMSC 驱动的肺转移被消除。通过抗体阻断 IL-4 也会减弱 LMSC 驱动的癌症向肺部转移。一致地，在 Th2 偏向 T-bet 缺陷型小鼠或接受 T-bet 缺陷型 T 细胞过继转移的裸鼠中，转移大大增强。在乳腺癌患者中也检测到 C3 水平增加。我们的结果表明，靶向 Th2-STAT6-C3-NETs 级联可能会减少乳腺癌向肺部的转移。
