外泌体Rab10通过激活肺泡上皮细胞CCL2-CCR2信号通路参与食管癌术后肺转移前微环境形成的分子调控机制及潜在临床应用研究

食管癌术后肺转移发生率高，预后差，缺少有效治疗手段，亟需明确其发生机制并提出防治策略。前期研究发现：（1）食管癌术后转移前微环境(Pre-metastatic niche, PMN)的形成与肺转移密切相关；（2）食管癌外泌体Rab10可与II型肺泡上皮细胞结合，促进PMN形成；（3）PMN中II型肺泡上皮细胞的CCL2-CCR2通路高度活化。因此，我们推测外泌体Rab10可通过激活II型肺泡上皮细胞中CCL2-CCR2通路，促进食管癌术后肺PMN和转移的形成。本课题围绕上述假说，利用已建立的食管癌术后自发肺转移模型，通过转录组学、蛋白质组学等探索外泌体Rab10活化II型肺泡上皮CCL2-CCR2轴的关键调控通路及分子；并在临床前模型和患者标本中进行功能与机制等验证，揭示外泌体Rab10对食管癌术后PMN形成的作用，及对肺转移的预测和治疗价值，为精准预测和治疗食管癌术后肺转移提供理论基础。

Esophageal cancer has a high incidence of pulmonary metastasis after primary tumor resection. Unfortunately, the prognosis of those patients is dismal and effective treatment is lacking. Therefore, it is urgent to explore the molecular mechanisms underlying the postoperative pulmonary metastasis and finally find the precise prevention and treatment strategies. In the previous study, we found that the pre-metastatic niche (PMN) formation is closely related to pulmonary metastasis; exosome Rab10 from esophageal cancer could be captured by type II alveolar epithelial cells to promote the formation of the PMN; and the CCL2-CCR2 pathway in type II alveolar epithelial cells is highly activated. Based on these findings, we hypothesized that exosome Rab10 might initiate and promote lung PMN formation by activating alveolar epithelial CCL2-CCR2 axis, and finally result in pulmonary metastasis. Based on the above hypothesis, this study aims to explore the key molecules and signaling pathways that involved in exosome Rab10-mediated CCL2-CCR2 axis activation in type II alveolar epithelial cells by transcriptomics, proteomics and other techniques in HNM007 pulmonary metastasis model. Furthermore, we will validate those molecule mechanisms in preclinical models and patient specimens to reveal the role of exosome Rab10 in lung PMN formation and the predictive effect and treatment strategies of Rab10 in pulmonary metastasis. This work will provide novel theoretical basis for precise prediction and treatment of postoperative pulmonary metastasis in esophageal cancer.