Regulation of lung cancer growth and metastasis by an actionable driver of vesicle biogenesis in the Golgi

高尔基体囊泡生物发生的可操作驱动因素对肺癌生长和转移的调节

基本信息

批准号：
10358493
负责人：
Jonathan M Kurie
金额：
$ 41.49万
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：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358493
关键词：
1-Phosphatidylinositol 4-Kinase Address Alleles Apoptosis Behavior Biogenesis Biological Blood Vessels CD8-Positive T-Lymphocytes CSF3 gene CXCL1 gene Cancer Model Cause of Death Cell Proliferation Cell Survival Cell physiology Cells Chromosomes Clinical Clinical Research Clinical Treatment Clinical Trials Coculture Techniques Development Disease Disseminated Malignant Neoplasm Docking Ectopic Expression Endothelial Cells Fibroblasts Fluorescence Foundations GOLPH3 gene Genetic Recombination Golgi Apparatus Granulocyte-Macrophage Colony-Stimulating Factor Growth IL8 gene Immunity Inflammation Inflammatory Interleukin-6 KRAS2 gene Lead Lentivirus Link Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Membrane Modeling Molecular Mus Myeloid Cells Neoplasm Metastasis Outcome Phosphoric Monoester Hydrolases Phosphotransferases Play Process Property Proteins Regulation Rest Role STC2 gene Site Structure TIMP1 gene Testing Therapeutic Tissues Tumor Volume Vascular Endothelial Growth Factors Vesicle Work aerosolized angiogenesis antagonist behavior influence cancer cell clinical development cytokine effective therapy improved inhibitor inorganic phosphate insight lung cancer cell metastatic process mutant neoplastic cell novel therapeutic intervention novel therapeutics phosphatidylinositol 4-phosphate small hairpin RNA small molecule therapeutically effective trafficking trans-Golgi Network tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

Few effective therapies are available for KRAS-mutant lung cancer (KMLC). To address this problem, we seek to elucidate the biological basis for KMLC growth and metastasis and to develop novel therapies on the basis of that improved understanding. Cancer cells secrete factors that promote tumor growth, matrix remodeling, angiogenesis, and inflammation, a process hereafter termed “malignant secretion”. Therapeutic strategies to block malignant secretion have not been developed. We have identified a chromosome 1q amplicon harboring and numerous regulators of vesicle biogenesis and trafficking, including phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a Golgi-dedicated kinase that generates phosphatidylinositol 4-phosphate (PI4P). We show that the viability and proliferative and invasive activities of 1q–amplified KMLC cells require PI4KIIIβ. A selective PI4KIIIβ antagonist preferentially induced apoptosis and inhibited the metastatic properties of 1q–amplified KMLC cells. On the basis of these findings, we hypothesize that high PI4KIIIβ levels promote KMLC growth and metastasis and confer vulnerability to PI4KIIIβ antagonists. To test this hypothesis, we propose in Aim 1 to an autochthonous PI4KIIIβ–expressing KMLC model and determine whether PI4KIIIβ enhances KMLC metastatic propensity and confers vulnerability to PI4KIIIβ antagonists. Our findings will elucidate the way in which PI4KIIIβ drives KMLC progression and may provide a foundation for new therapeutic approaches using PI4KIIIβ antagonists. We show that high PI4KIIIβ levels in 1q–amplified KMLC cells enhanced anterograde vesicular trafficking and stimulated the secretion of pro-survival and pro-metastatic factors. PI4KIIIβ–driven metastatic properties required Golgi phosphoprotein 3 (GOLPH3), a PI4P–tethered Golgi protein that promotes vesicle budding from the trans-Golgi network. Therefore, we postulate that PI4KIIIβ-dependent secretion is required to activate pro- metastatic processes in the tumor microenvironment and maintain the viability of 1q-amplified KMLC cells. To test this hypothesis, we will inactivate Golph3 in PI4KIIIβ-expressing autochthonous KMLCs and 1q-amplified orthotopic KMLCs. Resultant changes in tumor cell viability and inflammatory, stromal, and vascular cell functions in the tumor microenvironment will be measured. We will identify PI4KIIIβ-dependent secreted proteins that mediate these changes and elucidate how they exert these functions. Our findings will provide insight into how a secretory process activated by a chromosomal region that is frequently amplified in cancer maintains tumor cell viability and influences diverse processes in the tumor microenvironment. In summary, the evidence presented here links malignant secretion to a chromosomal region that is frequently amplified in KMLC and provides a basis for clinical studies to develop PI4KIIIβ antagonists as first- in-class inhibitors of malignant secretion. Our findings elucidate the molecular underpinnings of malignant secretion and show that chromosome 1q-amplified cancers are vulnerable to secretory blockade.

KRAS突变肺癌很少有效疗法（KMLC）。为了解决这个问题，我们试图阐明KMLC增长和转移的生物学基础并基于这种改善的理解发展新型疗法。癌细胞的秘密因素促进肿瘤生长，基质重塑，血管生成和注射，此后称为 “恶性分泌”。尚未制定阻止恶性分泌的治疗策略。我们已经确定了1q染色体植物的携带和囊泡生物发生的众多调节剂和运输，包括磷脂酰肌醇4-激酶IIIβ（PI4KIIβ），这是一种产生高尔基体的激酶磷脂酰肌醇4-磷酸（PI4P）。我们表明，生存能力，增殖和侵入性活动 1q -扩大的KMLC细胞需要PI4KIIIβ。选择性PI4KIIIβ拮抗剂优先诱导凋亡和抑制了1Q扩增的KMLC细胞的转移特性。根据这些发现，我们假设高PI4KIIIβ水平促进了KMLC的生长和转移以及对PI4KIIIβ拮抗剂的会议脆弱性。为了检验这一假设，我们在AIM 1中提出了表达kMLC模型的自围候PI4KIIIβ和确定PI4KIIβ是否增强了KMLC转移性倾向并承认易受PI4KIIIβ的脆弱性对手。我们的发现将阐明PI4KIIIβ驱动KMLC进展的方式，并可能提供使用PI4KIIIβ拮抗剂的新治疗方法基础。我们表明，在1q扩增的KMLC细胞中，高PI4KIIIβ水平增强了囊泡运输并刺激了促生物和促生物因素的分泌。 PI4KIIβ驱动的转移性特性需要Golgi磷蛋白3（Golph3），一种PI4P染色的高尔基蛋白，可促进囊泡从反式高尔基网络。因此，我们假设PI4KIIIβ依赖性分泌需要激活pro- 肿瘤微环境中的转移过程并维持1Q扩增的KMLC细胞的生存能力。到检验这一假设，我们将在表达PI4KIIβ的自动kMLC和1q扩增的PI4KIIIβ中灭活Golph3 原位KMLC。肿瘤细胞活力和炎症，基质和血管细胞的结果变化将测量肿瘤微环境中的功能。我们将识别pi4KIIβ依赖性分泌介导这些变化并阐明它们如何发挥这些功能的蛋白质。我们的发现将提供深入了解秘书过程是如何被染色体区域激活的，该过程经常在癌症中得到扩增维持肿瘤细胞活力，并影响肿瘤微环境中的不同过程。总而言之，此处提供的证据将恶性分泌与染色体区域联系起来经常在KMLC中扩增，并为临床研究提供了发展PI4KIIIβ拮抗剂的基础恶性分泌的课堂抑制剂。我们的发现阐明了恶性的分子基础分泌并表明染色体1q扩增的癌症容易受到秘书封锁的攻击。