瘤体诱导的淋巴管新生促进了新淋巴管的形成，有助于小鼠和人类的肿瘤细胞转移至淋巴结。血管萌发似乎是这一过程中的关键步骤。然而，淋巴管在肿瘤淋巴管新生过程中如何萌发尚未被完全确认。在这里，我们报告了在淋巴内皮细胞（LECs）中表达的S100A4通过调节糖酵解促进生长中的肿瘤中淋巴管萌发。在小鼠中，全身失去S100A4（S100A4-/-）或特定于LECs（S100A4ΔLYVE1）会导致肿瘤淋巴管新生受损，并破坏肿瘤细胞到哨兵淋巴结的转移。使用三维球体萌发试验，我们发现LECs中的S100A4对淋巴管萌发是必需的。进一步的研究揭示了S100A4对端细胞的位置和运动至关重要，在此过程中它激活了AMPK依赖性的糖酵解。此外，LECs中S100A4的表达在低氧情况下上调。这些结果表明S100A4是肿瘤诱导的淋巴管新生的新调节因子。针对LECs中的S100A4可能是淋巴性肿瘤转移的潜在治疗策略。©2022作者（s），在Springer Nature B.V.的独家许可下

Tumor-induced lymphangiogenesis promotes the formation of new lymphatic vessels, contributing to lymph nodes (LNs) metastasis of tumor cells in both mice and humans. Vessel sprouting appears to be a critical step in this process. However, how lymphatic vessels sprout during tumor lymphangiogenesis is not well-established. Here, we report that S100A4 expressed in lymphatic endothelial cells (LECs) promotes lymphatic vessel sprouting in a growing tumor by regulating glycolysis. In mice, the loss of S100A4 in a whole body (S100A4-/-), or specifically in LECs (S100A4ΔLYVE1) leads to impaired tumor lymphangiogenesis and disrupted metastasis of tumor cells to sentinel LNs. Using a 3D spheroid sprouting assay, we found that S100A4 in LECs was required for the lymphatic vessel sprouting. Further investigations revealed that S100A4 was essential for the position and motility of tip cells, where it activated AMPK-dependent glycolysis during lymphatic sprouting. In addition, the expression of S100A4 in LECs was upregulated under hypoxic conditions. These results suggest that S100A4 is a novel regulator of tumor-induced lymphangiogenesis. Targeting S100A4 in LECs may be a potential therapeutic strategy for lymphatic tumor metastasis.© 2022. The Author(s), under exclusive licence to Springer Nature B.V.