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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

基本信息

批准号：
9213276
负责人：
Jonathan M Kurie
金额：
$ 37.89万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9213276
关键词：
Address Adenocarcinoma Cell Alleles Area Biochemical Biological Biological Assay Breeding Carrier Proteins 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 Link Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Mesenchymal Microscopic Microtubules Modeling Motor Mus Mutation Neoplasm Metastasis Organelles Other Genetics Outcome Patients Pharmacology Physiological Property Proteins Public Health Regulation Research Research Personnel Resected Rest Scaffolding Protein Specimen Staining method Stains Structural Protein Structure of parenchyma of lung Subfamily lentivirinae Techniques Technology Testing Transcriptional Regulation Treatment Efficacy Vesicle Vimentin base cancer cell cell motility clinically relevant cohort effective therapy genetic manipulation improved in vivo intravital microscopy microscopic imaging mouse model mutant neoplastic cell novel therapeutic intervention outcome forecast prevent programs protein transport scaffold targeted agent therapeutic target tool trafficking transcription factor tumor

项目摘要

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.

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