Wang Hanghang, Hu Danjing, Cheng Chongsheng, Zhang Xiaoxin, Liu Junya, Tian Xinlun, Zhang Hongbing, Xu Kai-Feng
Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100053, China.
Sci China Life Sci. 2025 Jan 22. doi: 10.1007/s11427-024-2760-4.
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease affecting the lung, kidney, and lymphatic system with a molecular mechanism of tuberous sclerosis complex 2 (TSC2) mutations. Vascular endothelial growth factor D (VEGF-D), a ligand for vascular endothelial growth factor receptor 3 (VEGFR3), is a diagnostic biomarker of LAM and is associated with lymphatic circulation abnormalities. This study explored the interaction between LAM cells and lymphatic endothelial cells (LECs) and the effects of rapamycin on this interaction, which may help to identify new targets for LAM treatment. This study used direct and indirect cocultures of TSC2-null cells and LECs. The xenograft model was applied to explore the therapeutic feasibility. Single-cell sequencing revealed increased LECs in the lungs of LAM patients through activation of pathways involved in lymphangiogenesis. TSC2-null cells attracted LECs and promoted tube formation. VEGF-D/VEGFR3 was a key mediator of the above interaction. Rapamycin can directly inhibit recruitment but not the tube formation of LECs in vitro. The combination of rapamycin with VEGFR3 inhibitors not only enhanced the effect of rapamycin but also inhibited lymphatic related manifestations including the tube formation and the lymphatic metastasis. Our findings demonstrated that LAM cells recruit LECs and promote tube formation via VEGF-D/VEGFR3. Rapamycin only partially blocked this interaction. The synergistic effects of rapamycin and VEGFR3 inhibitors suggest a novel strategy for the treatment of LAM and other TSC2-mutated diseases.
淋巴管平滑肌瘤病（LAM）是一种罕见的肿瘤性疾病，影响肺、肾和淋巴系统，其分子机制为结节性硬化复合物2（TSC2）突变。血管内皮生长因子D（VEGF-D）是血管内皮生长因子受体3（VEGFR3）的配体，是LAM的诊断生物标志物，与淋巴循环异常有关。本研究探讨了LAM细胞与淋巴管内皮细胞（LEC）之间的相互作用以及雷帕霉素对这种相互作用的影响，这可能有助于确定LAM治疗的新靶点。本研究使用了TSC2基因缺失细胞与LEC的直接和间接共培养。应用异种移植模型探讨治疗可行性。单细胞测序显示，通过激活淋巴管生成相关通路，LAM患者肺中的LEC增加。TSC2基因缺失细胞吸引LEC并促进管腔形成。VEGF-D/VEGFR3是上述相互作用的关键介质。雷帕霉素在体外可直接抑制LEC的募集，但不能抑制其管腔形成。雷帕霉素与VEGFR3抑制剂联合使用不仅增强了雷帕霉素的效果，还抑制了包括管腔形成和淋巴转移在内的淋巴相关表现。我们的研究结果表明，LAM细胞通过VEGF-D/VEGFR3募集LEC并促进管腔形成。雷帕霉素仅部分阻断这种相互作用。雷帕霉素与VEGFR3抑制剂的协同作用为LAM和其他TSC2突变疾病的治疗提供了一种新策略。
