Regulation of lung cancer metastasis through transcriptional control of the Golgi apparatus

我们的目标是更好地了解KRAS突变肺癌(KMLC)转移的生物学基础和 在这种理解的基础上开发新的治疗方法。这一领域的进展可能 可能会对公众健康造成巨大影响，因为转移是 肺癌，目前对KMLC几乎没有有效的治疗选择。为了实现这一目标，我们 K-RasG12D共表达致小鼠肺腺癌转移 和p53R172H。我们的初步结果表明，ZEB1是KP小鼠转移的转录驱动因素，并且 多种上皮性肿瘤类型临床预后不良的预测因子，导致高尔基细胞器 更紧凑和集中，形成带状连接的脑池堆叠，并刺激囊泡在 顺行方向。ZEB1增加PAQR11的表达，PAQR11是高尔基体支架蛋白 ZEB1诱导的高尔基细胞器完整性和肿瘤细胞转移特性所必需的。在下拉分析中， PAQR11的支架结构域与囊泡共瘤蛋白结合，GTP酶调节囊泡萌发 以及沿着微管将货物运送到细胞中心的动力蛋白。 PAQR11缺失降低肺腺癌细胞的迁移、侵袭和转移活性 来源于KP小鼠和人KMLC细胞。高水平的肿瘤内PAQR11预示着较短的生存期 11个独立的人类肺癌队列的概要和对30多种肿瘤类型的泛癌分析。 根据我们的初步结果，我们假设KMLCs通过以下途径获得转移潜能 高尔基体的转录调控。 为了检验这一假设，我们提出了两个具体目标。在第一个目标中，我们将确定PAQR11 促进动力蛋白介导的高尔基体微型堆积和脑池的带状连接和堆积 创造一个集中的高尔基复合体，驱动顺行的囊泡运输，促进肿瘤细胞的运动。 在第二个目标中，我们将确定异位PAQR11表达促进转移的程度 自发产生的KMLCs。 如果我们的假设是正确的，这些发现将促进我们对KMLC发病机制的理解 细胞获得转移倾向，为该领域的研究人员提供了研究高尔基体的新工具 肺自然微环境中肿瘤细胞的动力学，对 肺腺癌转移的潜在原因，以及研究靶向药物的基础 ZEB1的介体在临床试验中预防KMLC转移。

Our goal is to better understand the biologic basis for metastasis of KRAS-mutant lung cancer (KMLC) 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 KMLC. Towards that goal, we generated KP mice, which develop metastatic lung adenocarcinoma owing to the co-expression of K-rasG12D and p53R172H. Our preliminary results show that Zeb1, a transcriptional driver of metastasis in KP mice and predictor of poor clinical outcome in multiple epithelial tumor types, caused the Golgi organelle to become more compact and centralized, form ribbon-linked cisternal stacks, and stimulate vesicle trafficking in the anterograde direction. ZEB1 increased the expression of PAQR11, a Golgi scaffolding protein that was required for ZEB1-induced Golgi organelle integrity and tumor cell metastatic properties. In pull-down assays, the scaffolding domain of PAQR11 bound to vesicle coatomer proteins, GTPases that regulate vesicle budding and tethering, and dynein motor proteins that transport cargo along microtubules towards the cell's center. PAQR11 depletion reduced the migratory, invasive, and metastatic activities of lung adenocarcinoma cells derived from KP mice and human KMLC cells. High intra-tumoral PAQR11 levels predicted shorter survival in a compendium of 11 independent human lung cancer cohorts and a pan-cancer analysis of over 30 tumor types. On the basis of our preliminary results, we hypothesize that KMLCs gain metastatic potential through transcriptional control of the Golgi apparatus. To test this hypothesis, we propose two Specific Aims. In the first Aim, we will determine whether PAQR11 facilitates the dynein-mediated transport of Golgi mini-stacks and ribbon-linking and stacking of cisternae to create a centralized Golgi complex that drives anterograde vesicle trafficking and promotes tumor cell motility. In the second Aim, we will determine the extent to which ectopic PAQR11 expression promotes the metastasis of spontaneously occurring KMLCs. If our hypothesis is correct, these findings will advance our understanding of the mechanisms by which KMLC cells gain metastatic propensity and provide researchers in the field with new tools to investigate Golgi dynamics in tumor cells in the native microenvironment of the lung, an improved understanding of the underlying causes of lung adenocarcinoma metastasis, and a basis for investigating agents that target mediators of Zeb1 in clinical trials to prevent KMLC metastasis.