MEN1调控ATII细胞神经内分泌恶性转化的基因组稳定性机制

基因组不稳定性是神经内分泌型肿瘤的显著特征，我们证实MEN1基因是神经内分泌型肺癌（P-NET）发病的关键抑癌基因，然而MEN1定向调控ATII细胞向神经内分泌型恶性转化的DNA损伤修复机制目前尚不清楚。本项目提出科学假设：MEN1突变或失活通过染色质结构及重塑异常引起DNA损伤修复程序紊乱，可能是控制上皮细胞来源肺癌细胞定向分化及治疗抗性产生的关键节点。本项目从已获得的组学数据的整合性分析入手，利用关键基因敲除及理化因素诱导的DNA损伤模型，探讨MEN1通路调控ATII细胞基因组稳定性及定向分化的规律及机制；建立小鼠原发性肺癌疾病模型，探讨MEN1基因失活导致的基因组不稳定性诱发肺癌细胞治疗抗性产生的细胞学基础及染色质组蛋白重建机制；开展基于疾病模型及发病机制的肺癌治疗精准医疗探索。这将有助于从染色质重塑角度深入理解肿瘤细胞DNA损伤修复、细胞定向分化及治疗抗性产生机制。

Genome instability is the prominent feature of neuroendocrine tumors. We confirmed that MEN1 is a key tumor suppressor gene for neuroendocrine lung cancer (P-NET). However, the mechanism of DNA damage repair regulated by MEN1 during neuroendocrine malignant transformation of ATII cells is unclear. We propose that MEN1 mutation or inactivation causes disorder of DNA damage repair program through abnormal chromatin structure and remodeling, which may be a key point for controlling the directional differentiation and treatment resistance of lung cancer derived from epithelial cells. In this project, we will utilize the model of DNA damage induced by key gene knockout and physical and chemical factors and integrated analysis of the obtained high throughout data to explore the rules and mechanisms of the genome stability and committed differentiation regulated by MEN1 in ATII cells; Establish a primary lung cancer model of mouse to demonstrate the cytological basis and chromatin histone remodeling mechanism of the lung cancer treatment resistance, which is caused by genome instability due to MEN1 gene inactivation. Explore precision medicine for lung cancer treatment based on animal disease models and pathogenesis. This project will reveal the mechanism of DNA damage repair, committed differentiation and therapeutic resistance of tumor cells through chromatin remodeling.