癌细胞干性的获得和维持是驱动转移的重要动力。SPARC在肿瘤中发挥重要作用，但在癌细胞干性方面极少报道。申请人前期发现SPARC在晚期肾癌组织高表达，并与肾癌转移和复发密切相关；体内和体外实验发现SPARC可显著促进肾癌细胞的转移。本项目中，我们进一步发现SPARC可能结合整合素α9β1并激活ILK/AKT/GSK3β/β-catenin通路，最终诱导BMI-1表达，增强肾癌细胞干性，促进肾癌转移。令人兴奋的是，本团队制备的新型SPARC单克隆中和抗体能有效抑制SPARC表达及肾癌细胞恶性表型。据此，申请人提出假设：SPARC单克隆抗体靶向SPARC并抑制其表达，减少SPARC与α9β1相互作用，进而阻止ILK对AKT/GSK3β/β-catenin/BMI-1信号的激活，最终抑制肾癌细胞干性和转移。后续研究将证实该假设。我们的研究将为晚期肾癌治疗提供新靶点，并为新型抗体药物研发奠定基础。

The acquisition and maintenance of cancer cell stemness is a vital factor driving RCC metastasis. SPARC plays an important role in cancer; however, the effect of SPARC on stemness of cancer cell is largely unknown. Our previous study showed overexpression of SPARC in advanced RCC tissues, SPARC was closely associated with recurrence and metastasis of RCC; results from in vitro and in vivo experiments showed SPARC could significantly enhance RCC cell metastasis. In this project, we further reveal that SPARC could interact with integrin α9β1 and subsequently activate ILK/AKT/GSK3β/β-catenin signaling pathway, induce the expression of BMI-1, enhance the stemness of RCC cell, and finally promote the metastasis of RCC cell. What excites people is that the novel SPARC monoclonal neutralizing antibody made by our team could effectively suppress the expression of SPARC as well as the malignant phenotype of RCC cell. Based on these, we propose that SPARC monoclonal antibody suppress SPARC expression, reduce the interaction between SPARC and integrin α9β1, subsequently repress the ILK-elicited activation of AKT/GSK3β/β-catenin/BMI-1 signal, and finally suppress the stemness and metastasis of RCC cell. This project will prove our hypothesis. We aim to establish SPARC as a novel therapeutic target for advanced RCC and lay the foundation for novel antibody drug development.