“种子土壤学说”表明肿瘤微环境对原位肿瘤及转移肿瘤细胞生长都是至关重要的。现已明确肿瘤细胞在转移前已对远处器官的微环境进行了适应性的调整。但这一过程的分子机制目前仍远未阐明。我们前期已发表文章报道: 高表达癌基因TBL1XR1可诱导食管癌细胞淋巴结转移(Gut)。同时我们观察到:裸鼠淋巴结在TBL1XR1高表达肿瘤细胞转移前已发生淋巴管新生; 近期我们预实验结果显示:①TBL1XR1可上调多个与外泌体组装/释放的基因并促进食管癌细胞外泌体分泌; ②这些外泌体中的多个miRNAs可导致淋巴结/肺部形成炎症微环境,并诱导内皮细胞间质化及肿瘤相关成纤维细胞转化; ③炎症微环境中的外泌体又可正反馈激活肿瘤细胞中多条信号通路, 进而增强肿瘤细胞干性及成瘤能力。本项目将承前启后，深层次解析癌基因TBL1XR1调控肿瘤细胞外泌体而诱导淋巴/肺肿瘤微环境以促进肿瘤远处转移的分子机制，并为肿瘤诊断治疗提供新的靶位点。

In according with the “seed and soil” hypothesis, the tumor microenvironment or niche plays important roles in the proliferation of both primary and metastatic tumor. It has been reported that the premetastatic niche in distant organ has been organized by the primary tumor cells before metastasis. However, the precise mechanism remains largely unclear. Previously, we have demonstrated in our published paper that overexpression of TBL1XR1 promotes lymphatic metastasis in esophageal squamous cell carcinoma (ESCC) (Gut. 2015 Jan; 64(1):26-36). Predominantly, we also observed that regional lymph nodes underwent reactive lymphangiogenesis prior metastasis. Moreover, we found that TBL1XR1 overexpression facilitated secretion of exosomes through upregulation of several genes associated with resemble and release of exosome. The exosomes regulted by TBL1XR1 could induce inflammatory microenvironment in the lymph nodes and lung, in accompanying with Endothelial-mesenchymal transition (EndoMT) and cancer-associated fibroblast (CAFs) formation. Meanwhile, the exosome released from endothelia and CAFs could positive feedback to enhance the stemness and tumorigenesis of metastatic tumor cells via activation multiple cancer stem cell-associated signaling pathways. Hence, in the current project, we aim to explore the biological function and underlying mechanism in which TBL1XR1-induced exosome promotes ESCC metastasis, which might provide new biomarkers and targets for the diagnosis and treatment of cancer.