SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer
SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer
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DOI：
10.1164/rccm.201510-2084oc
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发表时间：
2017-06-01
影响因子：
24.7
通讯作者：
McCaughan, Frank M.
中科院分区：
文献类型：
--
作者：
Correia, Lucia L.;Johnson, Jo-Anne;McCaughan, Frank M.
理由：提高肺癌的早期发现和化学预防是改善预后的关键。早期鳞状肺癌的病理生物学尚不清楚。我们已经表明，性别决定区Y-box 2 （SOX2）的扩增是该疾病发病机制的早期和一致的事件，但其功能致癌潜力仍不确定。我们在一种新的器官型系统中测试了SOX2表达失调的影响，该系统重现了鳞状癌发生的分子和微环境背景。目的：(1)建立一种能够概括人类疾病关键分子和表型特征的支气管发育不良体外模型；(2)验证SOX2解除调控是支气管发育不良早期发病的关键事件；(3)利用该模型进行发病机制和化学预防的研究。方法：我们设计了永生化支气管上皮细胞中癌基因的诱导激活。采用三维组织培养方法建立支气管发育不良的器官型模型。测量结果和主要结果：我们在体外重现了人支气管发育不良。SOX2解除管制驱动发育不良，而肿瘤启动子53的缺失是一个协同遗传事件，增强了发育不良表型。不受管制的SOX2改变了与癌症进展标志相关的关键基因。靶向抑制AKT可防止发育不良表型的发生。结论：在适当的遗传和微环境背景下，SOX2的急性解除可驱动支气管发育不良。这证实了其在人类细胞中的致癌潜力，并为SOX2解除管制的影响提供了新的见解。该模型可用于测试针对化学预防的治疗剂。
Rationale: Improving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown that amplification of sex-determining region Y-box 2 (SOX2) is an early and consistent event in the pathogenesis of this disease, but its functional oncogenic potential remains uncertain. We tested the impact of deregulated SOX2 expression in a novel organotypic system that recreates the molecular and microenvironmental context in which squamous carcinogenesis occurs.Objectives: (1) To develop an in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease; (2) to test the hypothesis that SOX2 deregulation is a key early event in the pathogenesis of bronchial dysplasia; and (3) to use the model for studies on pathogenesis and chemoprevention.Methods: We engineered the inducible activation of oncogenes in immortalized bronchial epithelial cells. We used three-dimensional tissue culture to build an organotypic model of bronchial dysplasia.Measurements and Main Results: We recapitulated human bronchial dysplasia in vitro. SOX2 deregulation drives dysplasia, and loss of tumor promoter 53 is a cooperating genetic event that potentiates the dysplastic phenotype. Deregulated SOX2 alters critical genes implicated in hallmarks of cancer progression. Targeted inhibition of AKT prevents the initiation of the dysplastic phenotype.Conclusions: In the appropriate genetic and microenvironmental context, acute deregulation of SOX2 drives bronchial dysplasia. This confirms its oncogenic potential in human cells and affords novel insights into the impact of SOX2 deregulation. This model can be used to test therapeutic agents aimed at chemoprevention.