Lung Cancer Stem Cell Program

我们将从主要在非吸烟者中发现的EGFR驱动的肺癌中识别和鉴定CSC，将这些发现与烟草诱导的K-RAS相关肿瘤进行比较，并检查支持肺CSC的癌前生态位。表型和功能鉴定之后将进行肺CSC分离、miRNA和基因表达分析、表观遗传学变化和对治疗的反应。我们将使用EGFR和K-RAS驱动的转基因和烟草致癌物诱导的小鼠模型、人类细胞系和肺癌患者的临床样本。对CSC生物学的分析将为肺CSC的药物试验和临床开发提供支持。具体目的1：人和小鼠肺癌来源的肺癌干细胞的鉴定和鉴定。A)在K-RAS驱动的肺癌中鉴定CSC；b)在EGFR驱动的肺癌中鉴定CSC；c)在癌前病变和烟草诱导的肿瘤发生过程中鉴定CSC；d)鉴定肺CSC的分子特征；2.调节肺CSC的存活和自我更新。A)遗传方法b)药理学方法c)毒理学方法

We will idenify and characterize CSC from EGFR-driven lung cancer that are mainly found in non-smokers, compare these findings with tabacco-induced K-Ras associated tumors, as well as examine the premalignant niche that supports lung CSC. Phenotypic and functional characterization will be followed by lung CSC isolation, analysis of miRNA and gene expression, epigenetic changes and responses to therapies. We will use EGFR and K-Ras driven transgenic and tabacco carcinogen-induced mouse models, human cell lines, and clinical samples from lung cancer patients. The analysis of CSC biology will support drug testing and clinical development of lung CSC directed therapies. Specific aim 1: identification and characterization of lung cancer stem cells derived from human and murine lung cancer. a)identification of CSC in K-Ras driven lung cancer b)identification of CSC in EGFR driven lung cancer c)identification of CSC in premalignant lung lesions and during tobacco induced tumorigenesis d)molecular characterization of lung CSC Specific aim 2: modulation of lung CSC survival and self-renewal. a)genetic approaches b)pharmacologic approaches c)toxicologic approaches