Regulation of Lung Cancer Metastasis by ZEB1

描述（由申请人提供）：我们的目标是更好地了解KRAS突变型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共卫生产生巨大影响，因为转移是肺癌死亡的主要原因，目前KRAS突变型肺腺癌的有效治疗选择很少。在这里，我们发现Zeb 1是上皮向间充质转化（EMT）的转录驱动因子，也是恶性进展的真正驱动因子，是多种上皮肿瘤类型临床结局不良的预测因子，它通过下调microRNA（miR-34 a和miR-148 a）诱导变形虫迁移开关。因此，我们推测Zeb 1通过下调miR-34 a和miR-148 a诱导变形虫开关来促进K-ras突变型肺腺癌的转移。为了验证这一假设，我们提出了两个具体目标。第一个目的是确定是否介质Zeb 1，促进变形虫开关所需的肺腺癌转移。目标1中的研究将纳入一种新的工具，用于肺中迁移性肿瘤细胞的体内显微成像，并将使用来自大型注释良好的人类肺癌组织库的标本进行验证。第二个目的是确定Mir 34基因位点（Mir 34 a、Mir 34 bc或两者）的失活是否诱导小鼠的转移，所述Mir 34基因位点在人肺癌中经常沉默，所述小鼠从突变型K-ras的表达发展为肺腺癌。如果我们的假设是正确的，这些发现将推进我们对Zeb 1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肺中肿瘤细胞的迁移动力学和肺腺癌转移的根本原因，并将为研究临床试验中靶向Zeb 1介质的药物提供基础。这些试验已经在进行中; miR-34 a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.