LTbetaR通过淋巴管内皮细胞调控肿瘤前哨淋巴结转移前微环境的形成及机制

Tumor metastasis is a leading cause of tumor mortality and the presence of tumor cells in sentinel lymph nodes (SLNs) is a key predictor of poor outcome in human cancer. The drainage of tumor-derived factors through the lymphatic system to the SLNs plays an important role in the pre-metastatic conditioning of the SLNs as supportive metastatic niches for tumor cells. This process illustrates the relevance of lymphatics to cancer biology. Lymphatic vessels facilitate metastasis via dynamic changes with lymphangiogenesis and expression of chemokines and cytokines by lymphatic endothelial cells (LECs). Therefore, targeting lymphangiogenic signaling pathways might be a potential tumor therapeutic strategy. Our previous studies showed that LIGHT-LTbetaR signaling plays a key role in lymphangiogenesis and LEC function under inflammation state, yet whether LIGHT-LTbetaR signaling plays a role in lymphangiogenesis and LEC function in tumor pre-metastatic niche formation is poorly understood. In this project, we will use specific conditional knockout mouse models combined with different analysis techniques to dissect the role of LIGHT-LTbetaR signaling in lymphangiogenesis and LEC function in the scenario of tumor pre-metastatic niche formation. This study will provide clues to better understand LN microenvironment and pre-metastatic niche formation, as well as shed a light on potential tumor therapeutic checkpoints.

肿瘤前哨淋巴结转移前微环境的形成是实体瘤发生前哨淋巴结转移的基础。淋巴管系统作为肿瘤因子与细胞向淋巴结迁移的通道和肿瘤细胞在淋巴结定植的基础，是否在淋巴结转移前微环境形成的过程中发挥作用、其调控机制如何，尚不清楚。我们的前期工作显示，LIGHT-LTbetaR信号通路调节炎症状态下淋巴管内皮细胞的增生活化，调控树突细胞和黑色素瘤从皮肤向淋巴结迁移和生存。由工作基础和文献调研，我们推测LIGHT-LTbetaR可能通过调节肿瘤引流淋巴管和前哨淋巴结的淋巴管内皮细胞，参与调节肿瘤转移前微环境的形成。本课题将利用不同条件性基因敲除小鼠，从LIGHT-LTbetaR调节淋巴管内皮细胞的角度入手，深入研究LIGHT-LTbetaR通路在肿瘤前哨淋巴结转移前微环境形成过程中的作用和机制。该研究将有助于理解肿瘤前哨淋巴结转移前微环境的形成机制，阐明淋巴管系统的新功能，为更加精准有效的肿瘤治疗提供新思路。

肿瘤前哨淋巴结转移前微环境的形成是实体瘤发生前哨淋巴结转移的基础。淋巴管系统作为肿瘤因子与细胞向淋巴结迁移的通道和肿瘤细胞在淋巴结定植的基础，是否在淋巴结转移前微环境形成的过程中发挥作用、其调控机制如何，尚不清楚。我们的研究首次显示，LIGHT-LTbetaR信号通路调节炎症状态下淋巴管内皮细胞的增生活化，调控树突细胞和黑色素瘤从皮肤向淋巴结迁移和生存。同时，我们发现，LEC上表达的LTbetaR相关分子X可将LEC分为两个亚群，且各自有不同的功能；LEC上X分子的表达对DC向DLN迁移和肿瘤细胞向SLN转移有明显的调控作用，我们的研究发现这一调控过程与CCR7-CCL21通路无关，这一抑制作用可能是通过调节LEC相关黏附分子发挥作用。我们的研究将有助于理解肿瘤前哨淋巴结转移前微环境的形成机制，阐明淋巴管系统的新功能，为更加精准有效的肿瘤治疗提供新思路。