自噬在肿瘤发生发展和耐药中的作用尚存很多争议，以往的研究模型局限于特定恶变程度的肿瘤细胞或自噬基因敲除小鼠自发肿瘤模型，未能监控正常细胞恶变全过程中自噬的发生情况并分析其因果关系。课题组前期通过全基因组测序，首次揭示了FAM135B是一个新型的食管鳞癌相关基因（高频扩增并与生存预后负相关），发现其与自噬相关蛋白ATG16L1存在相互作用，功能研究也证实FAM135B能够抑制自噬的发生。进一步的分子机制探索初步揭示mTOR能够上调FAM135B的蛋白水平。本项目将基于已构建成功的FAM135B转基因小鼠，通过给予食管癌诱发剂4-NQO处理，监测食管上皮细胞恶变全过程，深入研究FAM135B在肿瘤发生发展中的作用，阐明mTOR对FAM135B/ATG16L1的调控机制，明确FAM135B在自噬过程中的功能及其在肿瘤发生发展、化疗敏感性等方面的作用，为食管鳞癌的诊治提供有力的理论。

The role of Autophagy in tumor development, progression and chemoresistance is still in controversy. Previous research models were limited to tumor cells of certain malignant degree and autophagy related genes knockout mice, failing to track the history of malignant transformation of normal cells and analyze the possible causal relationship. In our previous study, we performed whole genome sequencing and figured out a novel esophageal squamous cell carcinoma (ESCC) driver gene FAM135B, which was frequently amplificated and significantly associated with poor survival. Further study revealed that FAM135B interacted with autophagy related gene ATG16L1 physically and suppressed autophagy. Additionally, we found that the protein level of FAM135B was upregulated by mTOR signaling pathway. To further investigate the role of FAM135B in ESCC development, we constructed FAM135B transgenic mice. In the present study, we seek to dissect the biological functions of FAM135B, with particular focus on autophagy in different stages of ESCC initiation and progression by using chemical agent 4-NQO to induce ESCC development in FAM135B transgenic mice. Further, we pursue to elucidate the underlying molecular mechanisms and illuminate the regulation relationship among mTOR, FAM135B and ATG16L1. Lastly, we will explore the clinical translation potential by targeting autophagy in FAM135B overexpression models in vitro and in vivo.