肿瘤相关成纤维细胞动员、招募、分化的机制研究

肿瘤微环境在癌症发生发展中发挥着非常关键的作用，其中肿瘤相关成纤维细胞(CAFs)是肿瘤微环境中含量最多的细胞之一，参与建立并重塑细胞外基质，并通过分泌多种细胞因子参与肿瘤-基质细胞的共同进化，是肿瘤侵袭转移发生的“驱动者”之一。因此靶向抑制CAFs的动员和招募将会成为肿瘤治疗的新策略。我们在前期实验中发现ESCC细胞通过分泌FGF2去动员FGFR2+纤维祖细胞增殖，继而招募入肿瘤组织中分化成CAFs，但CAFs的招募和分化分子机制尚不清楚。因此，本课题将寻找招募FGFR2+纤维祖细胞的关键趋化因子；应用全转录组测序及生物信息学技术揭示CAFs分化的分子机制；最后通过中和抗体阻断CAFs的动员和招募，确定其在肿瘤治疗的可行性。本项目研究将拓展我们对CAFs起源、动员、招募及分化的认识，为从源头上靶向抑制CAFs产生继而抑制肿瘤生成提供理论基础，具有重要的科学理论价值及临床指导价值。

Tumor microenvironment (TME) plays a critical role in cancer development and progression. Cancer-associated fibroblasts (CAFs) are one of the most infiltrated stroma cells in TME. Functionally, CAFs build up and remodel the extracellular matrix, accelerate tumor-stroma co-evolution via releasing numerous regulatory factors. Besides, CAFs are a main driver of the invasion-metastasis cascade in many cancer subtypes. Therefore, it is conceivable that mobilization and recruitment of CAFs might be new potential targets in cancer therapy. We previously found that FGFR2+ fibrocyte progenitors in bone marrow could be mobilized by FGF2 secreted from cancer cells. Moreover, they could be recruited into tumor tissue and differentiate into functional CAFs. However, the precise molecular mechanisms of CAFs recruitment and differentiation remain unclear. In this proposal, we plan to find the key chemokine responsible for recruiting FGFR2+ fibrocyte by in vitro and in vivo experiments. In addition, the molecular mechanisms underlying their differentiation will be addressed via high-throughput RNA-sequencing and bioinformatics analysis. Finally, the therapeutic potential of neutralizing antibodies blocking the process of CAFs mobilization and recruitment will be evaluated in mouse model. Our aim is to provide more insight for better understanding the origin, mobilization, recruitment and differentiation of CAFs, and to optimize CAFs targeting strategy for more effective cancer treatment.