软组织肉瘤是一类主要累及儿童的恶性肿瘤，发病率逐年上升，有效治疗手段缺乏，亟需发展新的治疗靶点。我们前期研究发现致癌基因ALK的新转录本ALK/ATI在软组织肉瘤中高表达。与ALK野生型及其融合蛋白主要定位于细胞浆不同， ALK/ATI蛋白不仅定位于肿瘤细胞的胞浆，还定位于胞核。外源表达ALK/ATI促进肿瘤细胞增殖及干细胞特性；进一步研究表明ALK/ATI蛋白可能具有较特异性的结合蛋白条带，但具体作用机制未明。本项目将结合生物信息学、基因编辑和蛋白互作实验技术等，阐明ALK/ATI被转运入核机制，鉴定与ALK/ATI相互作用的蛋白以及其参与介导调控软组织肉瘤细胞“干性”的机制，并明确ALK下游的PI3K/AKT、MAPK及STAT3/5信号通路在其中的作用，评价ALK抑制剂单用或联合传统化疗药物治疗ALK/ATI驱动的软组织肉瘤的安全性和有效性，从而为软组织肉瘤患者提供了新的治疗靶点。

Soft tissue sarcomas are malignant cancers with increasing incidence that mainly affect children’s patients. As effective treatments are lacking, it is urgent to develop new therapeutic targets for soft tissue sarcomas. The anaplastic lymphoma kinase (ALK) is an oncogene. In our previous study, we found a novel ALK transcript, ALK/ATI, was highly expressed in soft tissue sarcomas. Compared to the proteins encoded by the wild type or ALK fusion genes, ALK/ATI protein expressed not only in the cytoplasm, but also in the nucleus of sarcoma cells. ALK/ATI promoted proliferation and cancer stem-like characteristics of sarcoma cells, and our study indicated that ALK/ATI might interact with different specific binding proteins. However, the mechanism is unknown. In this study, based on bioinformatics, gene editing and protein interaction experiment technologies, etc, we aim to confirm the mechanism that ALK/ATI is transported into the nucleus and combined with stem cell-related transcription factors and regulated stem-like characteristics of sarcoma cells. We will also determine the role of ALK downstream signaling pathways including PI3K/AKT, MAPK and STAT3/5 in regulating stem-like characteristics. Meanwhile, we will evaluate the safety and efficacy of treatment with ALK inhibitors alone or combined with traditional chemotherapy drugs for patients with ALK/ATI-driven soft tissue sarcomas. Our study will lead to a new therapeutic target for patients of soft tissue sarcomas.