CD109经CCL2-CCR2轴诱导巨噬细胞极化对骨肉瘤肺转移的促进作用及机制研究

骨肉瘤（OS）是儿童青少年最常见的原发性骨恶性肿瘤，其肺转移是患者死亡的最主要原因, 5年生存率不足20%。巨噬细胞（Mφ）在肿瘤转移中发挥重要作用, 但其在OS肺转移中的作用和确切机制不详。我们新近发现一种驱动OS肺转移的关键分子CD109。临床样本、动物及细胞层面初步证实CD109 通过趋化和诱导Mφ 向M2 型极化发挥促进肿瘤转移作用, 进一步机制探索表明CD109诱导Mφ极化与CCL2-CCR2轴密切相关。由此，我们提出假设: CD109促进OS细胞分泌CCL2，趋化Mφ至肺转移灶并极化为M2型，进而促进OS肺转移。本项目拟在前期工作基础上，应用多色流式、活体成像、RNA测序、CCR2-/-小鼠模型等技术深入探讨CD109在驱动OS肺转移中调控M2型Mφ的确切作用和具体机制, 为今后开发以CD109为靶标的OS肺转移精准治疗策略提供理论依据。

Osteosarcoma (OS) is the most common primary bone malignant tumor in children and adolescents. Lung metastasis is the leading cause of death in OS patients, with a 5-year survival rate of less than 20%. Macrophage (Mφ) plays an important role in tumor metastasis, but its role and exact mechanism in OS lung metastasis remain unknown. Recently, we identified a key molecule CD109 that drives OS lung metastasis. Preliminary studies showed that CD109 promoted lung metastasis through Mφ chemotaxis and M2-type polarization from multiple levels including cells, animals, and clinical samples. Further research suggested that CD109-induced Mφ polarization was closely related to the CCL2-CCR2 axis. Therefore, we hypothesize that CD109 enhances Mφ chemotaxis and M2-type polarization through the CCL2-CCR2 axis, thereby promoting OS lung metastasis. Based on the previous work, this project intends to use multicolor flow cytometry, in vivo imaging, RNA sequencing, CCR2-/- mouse model，and other technologies to explore the exact role and specific mechanism of CD109 in driving OS lung metastasis via regulating M2-type Mφ. The implementation of this project provides a theoretical basis for developing precision therapies for OS lung metastasis by targeting CD109.