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，并 在加深理解的基础上开发新的治疗方法。该领域的进展可能 可能会对公共卫生产生巨大影响，因为转移是癌症死亡的主要原因 肺癌，目前 KMLC 的有效治疗方案很少。为了这个目标，我们 产生的 KP 小鼠，由于 K-rasG12D 的共表达而产生转移性肺腺癌 和p53R172H。我们的初步结果表明，KP 小鼠中转移的转录驱动因子 Zeb1 和 多种上皮肿瘤类型临床结果不佳的预测因子，导致高尔基细胞器变得 更加紧凑和集中，形成带状连接的池堆，并刺激囊泡在 顺行方向。 ZEB1 增加了 PAQR11 的表达，PAQR11 是一种高尔基体支架蛋白， ZEB1 诱导的高尔基体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外壳蛋白、调节囊泡出芽的 GTPases 结合 以及沿着微管向细胞中心运输货物的束缚和动力蛋白运动蛋白。 PAQR11 缺失降​​低了肺腺癌细胞的迁移、侵袭和转移活性 源自 KP 小鼠和人类 KMLC 细胞。肿瘤内高 PAQR11 水平预示着患者生存期较短 11 个独立的人类肺癌队列概要和 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 KMLC 通过以下方式获得转移潜力： 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 PAQR11 是否 促进高尔基体微型堆栈的动力蛋白介导的运输以及池的带状连接和堆叠 创建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 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，这些发现将增进我们对 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研究高尔基体的新工具 肺天然微环境中肿瘤细胞的动态变化，加深了对肿瘤细胞的理解 肺腺癌转移的根本原因，以及研究靶向药物的基础 Zeb1 介质在临床试验中预防 KMLC 转移。

项目成果

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

使用成骨细胞衍生的基质评估胶原蛋白修饰对癌细胞的影响。

• 发表时间: 2020-11
• 作者: Bota;Guo, Hou;Banerjee, Priyam;Chen, Yulong;Terajima, Masahiko;Yamauchi, Mitsuo;Kurie, Jonathan M
• 通讯作者: Kurie, Jonathan M

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

EMT 激活的分泌性和内吞性囊泡运输程序是肺癌中易受 PI4K2A 拮抗作用影响的基础。

• 发表时间: 2023-04-03
• 作者: Tan, Xiaochao;Xiao, Guan;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