癌基因TBL1XR1调控外泌体促食管癌转移的分子机制

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.

“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。

肿瘤是种子（肿瘤细胞）在合适的土壤（微环境）中生长的结果。外泌体在肿瘤微环境塑造以及肿瘤复发转移中发挥重要作用，是潜在的肿瘤诊断标志物和治疗靶点。本项目以癌基因TBL1XR1调控外泌体促进肿瘤转移为出发点，深入探讨肿瘤与转移微环境相互调控的机制，可能成为肿瘤临床诊治提供新标志物和潜在的治疗靶点。主要研究成果包括：1.发现TBL1XR1调控外泌体影响肿瘤微环境的机制。①我们发现外泌体TBL1XR1蛋白可穿梭进入淋巴内皮细胞，与STAT6结合并转录CCL21，促进肿瘤细胞跨内皮细胞迁移，增强淋巴结转移；②TBL1XR1通过外泌体miR-892b、miR-455-3p和miR-1266激活NF-κB和STAT3信号通路，调控炎症微环境（Cancer Res. 2016；Mol Cancer. 2017；Mol Ther Nucleic Acids. 2018）；③TBL1XR1结合蛋白CGI-99可转录上调IL6调控肺转移微环境（Oncogene 2017）。而RNF219转录上调LGALS3，促进破骨转移前微环境的形成（Advanced Science 2020）。 2.发现微环境反作用于肿瘤细胞促进转移复发的机制。①我们发现TL1XR1外泌体可显著诱导成骨细胞表达Wnt5a因子。Wnt5a通过ROR2/Siah2促进β-Catenin降解，促进肿瘤细胞在骨微环境中休眠（J Exp Med. 2019）；②我们发现AKIP1增强Wnt3a信号促进肝癌复发（Oncogene 2019）。③另外，我们发现多个TBL1XR1相关蛋白在治疗介导的微环境压力耐受中的功能（EMBO Mol Med 2019；Cancer Res 2018；Oncogene 2020）。项目已发表通讯作者论文13篇，其中3篇IF > 10；研究成果获科学奖励 3项（第一完成人）。