YAP介导转移相关成纤维细胞分泌COL11A1、MMPs促OSCC淋巴结被膜侵犯的机制研究

淋巴结被膜侵犯（ENE）是造成口腔鳞癌（OSCC）远处转移的重要因素。但还不清楚：肿瘤细胞是主动侵入并破坏被膜，还是由于其过度增殖、挤压导致被膜破裂？我们前期发现ENE+淋巴结具有高度增生的结缔组织，富含大量转移相关成纤维细胞（MAFs），其特征为YAP/TAZ显著激活，且增殖及胶原收缩能力较强。此外，胶原COL11A1在YAP激活型MAFs中显著上调，与YAP/TEAD、MMPs、EMT通路正相关。故推测YAP激活型MAFs可以通过调控转录因子TEAD进而促进COLl1A1及MMPs合成，诱导浸润型OSCC细胞形成，促进其主动突破淋巴结被膜。本项目拟分析MAFs中YAP/TEAD通路如何调控COLl11A1及MMPs合成，通过体内外模型揭示YAP激活型MAFs调控浸润型OSCC细胞产生的机制，为降低ENE发生率，抑制OSCC远处转移提供新的治疗思路。

Lymph node extranodal extension (ENE) is an important factor for distant metastasis of oral squamous cell carcinoma (OSCC). However, it is not clear whether the tumor cells actively invade and destroy the capsule, or the ENE is simply caused by its excessive proliferation and extrusion? We previously found that ENE+ lymph nodes had extensive desmoplasia, filled with metastasis-associated fibroblasts (MAFs), characterized by significant activation of YAP/TAZ signaling and strong proliferation and collagen contraction ability. In addition, COL11A1 was significantly up-regulated in YAP activated MAFs, which was positively correlated with YAP/ TEAD, MMPs and EMT pathways. It is speculated that YAP activated MAFs can promote the synthesis of COL1A1 and MMPs by regulating the transcription factor TEAD, induce the formation of invasive OSCC cells, and finally promote the active breakthrough of lymph node capsule. This project aims to analyze how YAP/TEAD pathway regulates the synthesis of COL11A1 and MMPs in MAFs, and reveal the mechanism of YAP activated MAFs regulating the production of invasive OSCC cells through in vivo and in vitro models, so as to provide a new therapeutic idea for reducing the incidence of ENE and inhibiting the distant metastasis of OSCC.