间质型CAF细胞调控SCUBE3/Smad信号通路介导肺癌细胞肝转移定植和适应的机理研究

EMT是肿瘤向血管解离扩散的主要驱动力，但肿瘤在远端组织适应和进展（转移定植）的机理尚不清楚。我们前期在肺癌肝转移患者组织中发现一种间质型肿瘤相关成纤维细胞CAFMet，其增殖、迁移和促血管生成能力显著增强，推测它可能作为基质细胞与肺癌共转移并参与建立转移微环境。进一步研究发现CAFMet通过FAP诱导肺癌细胞分泌SCUBE3进而激活Smad2通路促进转移定植。这可能是CAF介导肺癌在转移靶器官适应进展的新机制。本研究拟：1）通过组学和功能实验解析CAFMet通过FAP刺激SCUBE3分泌的机理；2）探讨SCUBE3通过激活Smad2通路上调相关效应分子表达进而建立局部促进增殖、血管新生和转移微环境的机理；3）在动物模型和临床标本上明确CAFMet具有远端迁移，并促进肿瘤转移定植的功能。以期阐明CAFMet介导肺癌在远端组织转移定植的分子机理，为肺癌转移的诊断、预警和药物研发提供分子标志。

Epithelial to mesenchymal transition (EMT) is the main driver for the dissemination and spread of tumor cells to blood vessels. However, mechanisms of the adaptation and progression of disseminated tumor cells (metastatic colonization) on distant and foreign tissues is still unclear. In our previous work, we disclose a cancer-associated fibroblast with mesenchymal phenotype (CAFMet) in the primary tissue of lung cancer patients with liver metastases, which show significantly increased proliferation, migration and angiogenic ability. It is speculated that CAFMet may act as stromal cells and co-metastasize with lung cancer cells participating in the establishment of metastatic niche. Further studies indicate that CAFMet induced lung cancer cells to secrete SCUBE3 by FAP, which activates Smad2 pathway to promote metastatic colonization. The potential mechanism may be a new approach, by which CAF promote adaptation of lung cancer on foreign tissues. In this study, we intends to: 1) elucidate the mechanisms of CAFMet stimulating SCUBE3 secretion through FAP by employing omics and functional ways; 2) explore the mechanisms that SCUBE3 upregulating the expression of relevant effector molecules by activating the Smad2 pathway to establish a microenvironment to promote proliferation, angiogenesis and metastasis; 3) validate the function of CAFMet that promotes tumor metastasis and colonization on animal models and clinical specimens. Our aim is to uncover the molecular mechanisms of CAFMet-mediated lung cancer metastasis and colonization in distant tissues and organs, and provide molecular markers for the diagnosis and early warning metastasis as well as anti-metastasis drug development of lung cancer.