Ewing肉瘤可起源于人骨髓间充质干细胞hMSCs，但hMSCs如何转化为Ewing肉瘤迄今未明。前期我们报道：HDGF为致瘤因子，促进Ewing肉瘤生长及转移。近期预实验发现：HDGF可促进hMSCs体外恶性转化，而HDGF与融合蛋白EWS-FLI1共表达则进一步使hMSCs呈现近似Ewing肉瘤的表型，提示HDGF在hMSCs恶变过程起重要作用，并可能协同EWS-FLI1促进Ewing肉瘤发生；同时，我们发现HDGF可上调EWS-FLI1表达，并可能与EWS-FLI1协同增强恶性转化因子AP-1的活性。本项目将在前期研究基础上，从细胞、动物水平，并结合临床样本，深入探明HDGF与EWS-FLI1协同调控AP-1信号通路促进hMSCs恶性转化的分子机制及生物学功能，为寻找新型靶向肿瘤干细胞治疗策略提供实验依据。

Ewing sarcoma (ES) can originate from human bone marrow mesenchymal stem cells (hMSCs), but the “initial events” that leads to ES development has remained partially understood. Our previous studies demonstrated that HDGF acts as an oncogenic factor that promotes the growth and metastasis of ES. Our preliminary data showed that HDGF promotes the vicious transformation of hMSCs in vitro, and what is more, the co-expression of HDGF and EWS-FLI1 results in a change in hMSCs phenotype towards one that is similar to Ewing sarcoma cells, suggesting that HDGF could play an important role in the malignant transformation of hMSCs, facilitated by EWS-FLI1 to initiate ES development. Meanwhile, we found that HDGF can up-regulate the expression of EWS-FLI1 and may act in synergy with EWS-FLI1 to enhance the activity of AP-1. Building on these findings, this project aims to elucidate, through ex vivo cellular experiments, in vivo animal studies as well as clinical biopsy samples, the molecular mechanism and biological function through which HDGF and EWS-FLI1 act via the activation of the downstream AP-1 signaling pathway to advance the cellular transformation of hMSCs. This project would provide experimental basis for seeking new therapeutic strategy targeting tumor stem cells.