Regulation of Lung Cancer Metastasis by ZEB1

描述(申请人提供)：我们的目标是更好地了解KRAS突变肺腺癌转移的生物学基础，并在此基础上开发新的治疗方法。这一领域的进展可能会对公众健康产生巨大的影响，因为转移是肺癌的主要死亡原因，而目前对KRAS突变的肺腺癌几乎没有有效的治疗选择。在这里，我们证明了ZEB1，一种上皮向间充质转化(EMT)的转录驱动因素，以及恶性进展的真正驱动因素，以及多种上皮性肿瘤类型中不良临床结果的预测因子，通过下调microRNAs(miR-34a和miR-148a)诱导了一种阿米巴样的迁移开关。因此，我们推测ZEB1通过下调miR-34a和miR-148a的表达而诱导变形体开关，从而促进K-ras突变肺腺癌的转移。为了检验这一假设，我们提出了两个具体目标。第一个目的是确定促进阿米巴转换的ZEB1介体是否对于肺腺癌转移是必需的。AIM 1上的研究将结合一种新的工具，用于在体内对肺部移行肿瘤细胞进行显微成像，并将使用来自大型、注释良好的人类肺癌组织库的样本进行验证。第二个目的是确定在人类肺癌中经常沉默的miR34基因位点(Mir34a、Mir34bc或两者)的失活是否会导致突变K-ras表达导致肺腺癌小鼠的转移。如果我们的假设是正确的，这些发现将促进我们对ZEB1促进转移机制的理解，将为该领域的研究人员提供新的工具来研究肿瘤细胞在肺内的迁移动力学和肺腺癌转移的潜在原因，并将为在临床试验中研究针对ZEB1介导物的药物提供基础。这样的试验已经在进行中；miR-34a脂质体颗粒目前正在晚期癌症患者的I期临床试验中进行测试。

DESCRIPTION (provided by applicant): Our goal is to better understand the biologic basis for metastasis of KRAS-mutant lung adenocarcinoma and to develop novel therapeutic approaches on the basis of that improved understanding. Progress in this area could potentially have a tremendous public health impact because metastasis is the primary cause of death from lung cancer, and there are currently few effective therapeutic options for KRAS-mutant lung adenocarcinoma. Here, we show that the Zeb1, a transcriptional driver of epithelial-to-mesenchymal transition (EMT) and bonafide driver of malignant progression and predictor of poor clinical outcome in multiple epithelial tumor types, induces an amoeboid migratory switch through the downregulation of microRNAs (miR-34a and miR-148a). Thus, we postulate that Zeb1 promotes metastasis of K-ras-mutant lung adenocarcinoma by inducing an amoeboid switch through the downregulation of miR-34a and miR-148a. To test this hypothesis, we propose two Specific Aims. The first Aim is to determine whether mediators of Zeb1 that promote an amoeboid switch are required for lung adenocarcinoma metastasis. The studies in Aim 1 will incorporate a new tool for in vivo microscopic imaging of migratory tumor cells in the lung and will be validated using specimens from a large, well-annotated human lung cancer tissue bank. The second Aim is to determine whether inactivation of Mir34 gene loci (Mir34a, Mir34bc, or both), which are frequently silenced in human lung cancer, induces metastasis in mice that develop lung adenocarcinoma from expression of mutant K-ras. If our hypothesis is correct, these findings will advance our understanding of the mechanisms by which Zeb1 promotes metastasis, will provide researchers in the field with new tools to investigate the migratory dynamics of tumor cells in the lung and the underlying causes of lung adenocarcinoma metastasis, and will provide a basis for investigating agents that target mediators of Zeb1 in clinical trials. Such trials are already underway; miR-34a liposomal particles are currently being tested in a phase I clinical trial in patients with advanced cancer.