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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：
10531617
负责人：
Jonathan M Kurie
金额：
$ 43.45万
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/10531617
关键词：
1-Phosphatidylinositol 4-Kinase Acceleration Address Alleles Behavior Biogenesis Biological Blood Vessels CD8-Positive T-Lymphocytes CSF3 gene CXCL1 gene Cancer Model Cause of Death Cell Proliferation Cell Survival Cell physiology Cell secretion Cells Chromosomes Clinical Clinical Research Clinical Treatment Clinical Trials Coculture Techniques Dedications 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 Induction of Apoptosis Inflammation Inflammatory Interleukin-6 Invaded KRAS2 gene 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 Protein Secretion Proteins Regulation Rest Role STC2 gene Site Structure TIMP1 gene Testing Therapeutic Tissues Tumor Promotion 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.

对于KRAS基因突变的肺癌几乎没有有效的治疗方法 (KMLC)。为了解决这个问题，我们试图阐明KMLC生长和转移的生物学基础。并在这种理解的基础上开发新的治疗方法。癌细胞分泌的因子促进肿瘤生长、基质重塑、血管生成和炎症，这一过程此后被称为 “恶性分泌物”。阻断恶性分泌物的治疗策略尚未开发出来。我们已经鉴定出一个含有囊泡生物发生调控因子的染色体1Q扩增子。和贩运，包括磷脂酰肌醇4-激酶IIIβ(PI4KIIIβ)，一种高尔基体专用的激酶，能产生磷脂酰肌醇4-磷酸(PI4P)。我们证明了它的生存能力、增殖能力和侵袭能力 1Q扩增的KMLC细胞需要PI4KIIIβ。选择性PI4KIIIβ拮抗剂优先诱导细胞凋亡和抑制1Q扩增的KMLC细胞的转移特性。根据这些发现，我们假设高水平的PI4KIIIβ促进KMLC的生长和转移，并增加对PI4KIIIβ拮抗剂的易感性。为了验证这一假设，我们在目标1中提出了一个表达PI4KIIIβ的本源KMLC模型和确定PI4KIIIβ是否增加了KMLC的转移倾向并增加了PI4KIIIβ的易感性对抗者。我们的发现将阐明PI4KIIIβ驱动KMLC进展的方式，并可能提供一种为使用PI4KIIIβ拮抗剂的新治疗方法奠定基础。我们发现在1Q扩增的KMLC细胞中高水平的PI4KIIIβ促进了顺行的囊泡运输并刺激促生存和促转移因子的分泌。PI4KIIIβ驱动的转移特性必需的高尔基体磷酸蛋白3(GOLPH3)，一种PI4P拴系的高尔基体蛋白，促进来自跨高尔基山脉网络。因此，我们推测PI4KIII型β依赖的分泌物需要激活PI4KIIIPRO。在肿瘤微环境中的转移过程，并维持1Q扩增的KMLC细胞的活力。至验证这一假设，我们将灭活PI4KIIIβ表达的固有KMLCs中的GOLPH3并1Q-扩增原位肾小管上皮细胞。由此引起的肿瘤细胞活性以及炎性、间质和血管细胞的变化将测量肿瘤微环境中的功能。我们将鉴定依赖于PI4KIIIβ的分泌物调节这些变化的蛋白质，并阐明它们如何发挥这些功能。我们的发现将提供深入了解在癌症中经常被扩增的染色体区域如何激活分泌过程维持肿瘤细胞的活性并影响肿瘤微环境中的不同过程。总而言之，这里提出的证据将恶性分泌物与染色体区域联系在一起在KMLC中频繁扩增，为临床研究开发PI4KIIIβ拮抗剂提供了基础一类抑制恶性分泌物的药物。我们的发现阐明了恶性肿瘤的分子基础。并表明，1Q染色体扩增的癌症很容易受到分泌阻断的影响。