Nanog在粘液型肺腺癌中的功能和机制研究

Lung cancer is one of the most devastating diseases worldwide. Animal models highly recapitulating the lung tumorigenesis process have been proven to be invaluable for our current understanding of molecular mechanisms in lung cancer development as well preclinical translational studies. Clinical studies have shown that certain human lung adenocarcinoma contains mucin overexpression and production and this subtype of lung cancer displays a high malignancy and the patients are frequently associated with poor prognosis. Unfortunately, there is no animal model that closely mimics this subtype of lung adenocarcinoma with mucin production currently. Here we have presented data to support that we have established a novel mouse model of lung adenocarcinoma with mucin production through the intercrossing of certain gene alleles. We will then perform detailed pathological analyses of lung tumors from this animal model and make a systematic comparative study of mouse and human lung adenocarcinoma with mucin production. We will decipher the molecular mechanism involved in mucin production and uncover the essential role of mucin production in lung adenocarcinoma initiation and progression. Lastly, we will take advantage of this animal model for small compound treatment for testing its inhibitory efficacy and perform the preclinical translational study. This work will hopefully improve our current understanding about how lung adenocarcinoma with mucin production initiate and progress and provide theoretical basis for clinical lung cancer treatment.

肺癌是当今全球范围内危害性最大的疾病之一。以往的研究已经充分表明肺癌动物模型对于我们深入理解肺癌发病过程并进行临床前的转化医学研究是非常重要的。临床的肺腺癌样本中存在着黏蛋白过度分泌的现象，并且这类肿瘤往往恶性程度较高，患者预后较差；而目前国际上并没有动物模型能够模拟肺粘液腺癌的发病过程。因此，在前期工作中我们利用临床样本鉴定出与粘液性腺癌发生发展高度相关的基因改变，建立了肺粘液腺癌小鼠模型，并对此动物模型来源的肺粘液腺癌进行病理学分析和鉴定，此模型的建立对本研究具有重要的理论意义和现实意义。后续我们将比较性地研究此动物模型与临床肺粘液腺癌的病理学异同，阐明黏蛋白过度分泌的分子机理并揭示其在肺粘液腺癌发生发展过程中的重要作用；并利用该动物模型进行小分子抑制剂的药效评估和治疗研究。本研究将有可能利用首次建立肺粘液腺癌的动物模型并为该亚型肺癌的发病分子机制及其临床治疗奠定坚实的理论基础。

本项目已按计划开展对Nanog在粘液性肺腺癌中的功能和机制的研究。通过构建KrasLSL-G12D/+; Lkb1flox/flox; Nanogflox/flox（KLN）小鼠模型和肺癌临床样本的整合性研究，对Nanog在粘液性肺腺癌发生发展过程中的功能和机制进行了深入分析。并利用KLN小鼠模型，开展了靶向Nanog缺陷型粘液性肺腺癌的治疗策略研究。我们发现Nanog是维持KL肿瘤干性的重要因子；敲除Nanog可启动胃分化程序并促进粘液性腺癌生长；人粘液性肺腺癌中存在NANOG和LKB1共丢失；阻断Notch通路显著抑制Nanog缺陷型小鼠肿瘤的粘液化；粘液性肺腺癌对苯乙双胍治疗明显抵抗；苯乙双胍联合Notch通路抑制剂抑制Nanog缺陷型粘液性肺腺癌生长。研究结果为治疗Nanog缺陷型粘液性肺腺癌提出新的干预策略。