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: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062880
• 关键词: Address; Adenocarcinoma Cell; Alleles; Area; Biochemical; Biological; Biological Assay; Breeding; Cause of Death; Cell Line; Cells; Clinical; Clinical Trials; Coatomer Protein; DNA Sequence Alteration; Disease; Dynein ATPase; Electrons; Enterobacteria phage P1 Cre recombinase; Epithelial; Epithelial Cells; Fluorescence Recovery After Photobleaching; Genetic Recombination; Genetic Transcription; Goals; Golgi Apparatus; Golgi Targeting; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Invaded; KRAS2 gene; Lentivirus; Link; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mesenchymal; Microscopic; Microtubules; Modeling; Motor; Mus; Mutation; Neoplasm Metastasis; Nonmetastatic; Organelles; Other Genetics; Outcome; Patients; Pharmacology; Physiological; Prognosis; Property; Proteins; Public Health; Regulation; Research; Research Personnel; Resected; Rest; Scaffolding Protein; Specimen; Stains; Structural Protein; Structure; Structure of parenchyma of lung; Techniques; Technology; Testing; Transcriptional Regulation; Vesicle; Vimentin; base; cancer cell; cell motility; clinically relevant; cohort; effective therapy; genetic manipulation; improved; in vivo; intravital microscopy; lung cancer cell; microscopic imaging; mouse model; mutant; neoplastic cell; novel therapeutic intervention; prevent; programs; protein transport; scaffold; targeted agent; therapeutic target; therapeutically effective; tool; trafficking; transcription factor; tumor

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.

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至 根据这种改善的理解，开发新型的治疗方法。在这个领域的进展可能 有可能产生巨大的公共卫生影响，因为转移是导致死亡的主要原因 肺癌，目前几乎没有有效的KMLC治疗选择。达到这个目标，我们 产生的KP小鼠，由于K-Rasg12d的共表达而形成转移性肺腺癌 和p53r172h。我们的初步结果表明，Zeb1是KP小鼠转移的转录驱动器， 预测多种上皮肿瘤类型的临床结果不良，导致高尔基细胞器变为 更紧凑，集中式，形成带有带状连接的蓄水池堆栈，并刺激囊泡运输 顺行向。 Zeb1增加了PAQR11的表达，Paqr11是一种高尔基脚手架蛋白 Zeb1诱导的高尔基细胞器完整性和肿瘤细胞转移性特性所需。在下拉测定中， PAQR11的脚手架结构域结合到囊泡外套蛋白，GTPase，调节囊泡芽 以及绑扎和动力蛋白运动蛋白，可将货物沿着微管运输到细胞中心。 PAQR11耗尽减少了肺腺癌细胞的迁移，侵入性和转移活性 源自KP小鼠和人类KMLC细胞。高肿瘤内PAQR11水平预测在A中较短的存活率 11种独立人类肺癌队列的纲要和30多种肿瘤类型的Pan-Cancer分析。 根据我们的初步结果，我们假设KMLC通过 高尔基体的转录控制。 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，我们将确定是否PAQR11 促进高尔基小型堆栈的动力蛋白介导的运输，并将水箱的链接和叠加到堆积 创建一种集中的高尔基体配合物，可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PAQR11表达促进转移的程度 自发发生的KMLC。 如果我们的假设是正确的，这些发现将提高我们对KMLC的机制的理解 细胞获得转移性倾向，并为该领域的研究人员提供研究高尔基的新工具 肺天然微环境中肿瘤细胞的动力学，对 肺腺癌转移的根本原因，以及研究靶向的药物的基础 Zeb1的介体在临床试验中，以防止KMLC转移。

项目成果

EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer.

• 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.

Use of osteoblast-derived matrix to assess the influence of collagen modifications on cancer cells.

• DOI: 10.1016/j.mbplus.2020.100047
• 发表时间: 2020-11
• 期刊: Matrix biology plus
• 作者: Bota-Rabassedas N;Guo HF;Banerjee P;Chen Y;Terajima M;Yamauchi M;Kurie JM
• 通讯作者: Kurie JM