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

Regulation of lung cancer metastasis through transcriptional control of the Golgi apparatus
通过高尔基体的转录控制调节肺癌转移
批准号:
10062880
负责人:
Jonathan M Kurie
金额:
$36.6万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-12-01 至 2022-10-31

项目摘要

项目成果

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中文摘要
翻译
我们的目标是更好地了解KRAS突变型肺癌(KMLC)转移的生物学基础, 在此基础上开发新的治疗方法。这方面的进展可以 潜在地具有巨大的公共卫生影响,因为转移是癌症死亡的主要原因。 肺癌,并且目前对于KMLC几乎没有有效的治疗选择。为了实现这一目标,我们 产生KP小鼠,其由于K-rasG 12 D的共表达而发生转移性肺腺癌 和p53 R172 H。我们的初步结果表明,Zeb 1,一个在KP小鼠中转移的转录驱动因子, 在多种上皮性肿瘤类型中预测不良临床结果,导致高尔基体细胞器成为 更紧凑和集中,形成带状连接的池堆栈,并刺激囊泡运输, 顺行方向ZEB 1增加了PAQR 11的表达,PAQR 11是一种高尔基体支架蛋白, ZEB 1诱导的高尔基体细胞器完整性和肿瘤细胞转移特性所需的。在下拉测定中, PAQR 11的支架结构域与囊泡外被体蛋白结合,所述囊泡外被体蛋白是调节囊泡出芽的GTP酶 以及沿着沿着微管向细胞中心运输货物的动力蛋白马达蛋白。 PAQR 11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。肿瘤内高PAQR 11水平预示着在一个肿瘤患者中生存期较短。 11个独立的人类肺癌队列的概要和超过30种肿瘤类型的泛癌症分析。 基于我们的初步结果,我们假设KMLCs通过以下途径获得转移潜能: 高尔基体的转录控制。 为了验证这一假设,我们提出了两个具体目标。在第一个目标中,我们将确定PAQR 11是否 促进动力蛋白介导的高尔基体微堆叠的运输以及脑池的带状连接和堆叠, 产生一个集中的高尔基复合体,驱动顺行囊泡运输并促进肿瘤细胞运动。 在第二个目标中,我们将确定异位PAQR 11表达促进转移的程度。 自发发生的KMLCs。 如果我们的假设是正确的,这些发现将促进我们对KMLC机制的理解。 细胞获得转移倾向,并为该领域的研究人员提供了研究高尔基体的新工具 在肺的天然微环境中肿瘤细胞的动力学, 肺腺癌转移的根本原因,以及研究靶向 在临床试验中使用Zeb 1介导剂来预防KMLC转移。
英文摘要
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.
期刊论文(2)
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会议论文
DOI: 10.1172/jci165863
发表时间: 2023-04-03
期刊: JOURNAL OF CLINICAL INVESTIGATION
影响因子: 15.9
作者: [Tan, Xiaochao, Xiao, Guan-Yu, Wang, Shike, Shi, Lei, Zhao, Yanbin, Liu, Xin, Yu, Jiang, Russell, William K., Creighton, Chad J., Kurie, Jonathan M.]
通讯作者: Kurie, Jonathan M.
DOI: 10.1016/j.mbplus.2020.100047
发表时间: 2020-11
期刊: Matrix biology plus
影响因子: --
作者: [Bota-Rabassedas N, Guo HF, Banerjee P, Chen Y, Terajima M, Yamauchi M, Kurie JM]
通讯作者: Kurie JM
Elucidating pro-metastatic collagen modifying activities of lysyl hydroxylase 2
A pro-metastatic secretory pathway activated by p53 loss in lung cancer
Elucidating pro-metastatic collagen modifying activities of lysyl hydroxylase 2
A pro-metastatic secretory pathway activated by p53 loss in lung cancer
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