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

• 批准号: 10061572
• 负责人: Jonathan M Kurie
• 金额: $ 45.04万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/10061572
• 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; behavior influence; cancer cell; clinical development; cytokine; effective therapy; improved; inhibitor/antagonist; 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

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 突变肺癌的有效治疗方法很少 （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 并在加深理解的基础上开发新的疗法。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，这一过程在下文中称为 “恶性分泌物”。尚未开发出阻止恶性分泌的治疗策略。 我们已经鉴定出包含囊泡生物发生的染色体 1q 扩增子和众多调节因子 和运输，包括磷脂酰肌醇 4-激酶 IIIβ (PI4KIIIβ)，一种高尔基体专用激酶，可产生 磷脂酰肌醇 4-磷酸 (PI4P)。我们证明了细胞的活力、增殖和侵袭活性 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 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 PI4KIIIβ 水平促进 KMLC 生长和转移，并导致对 PI4KIIIβ 拮抗剂的脆弱性。 为了检验这一假设，我们在目标 1 中提出了表达 PI4KIIIβ 的本地 KMLC 模型，并且 确定 PI4KIIIβ 是否增强 KMLC 转移倾向并赋予 PI4KIIIβ 易感性 对手。我们的研究结果将阐明 PI4KIIIβ 驱动 KMLC 进展的方式，并可能提供 为使用 PI4KIIIβ 拮抗剂的新治疗方法奠定了基础。 我们发现 1q 扩增的 KMLC 细胞中高 PI4KIIIβ 水平增强了顺行性囊泡运输 并刺激促生存和促转移因子的分泌。 PI4KIIIβ 驱动的转移特性 所需的高尔基体磷蛋白 3 (GOLPH3)，一种 PI4P 束缚的高尔基体蛋白，可促进囊泡出芽 跨高尔基体网络。因此，我们假设 PI4KIIIβ 依赖性分泌是激活前体所必需的。 肿瘤微环境中的转移过程并维持 1q 扩增的 KMLC 细胞的活力。到 为了检验这个假设，我们将在表达 PI4KIIIβ 的本地 KMLC 和 1q 扩增的细胞中灭活 Golph3 原位 KMLC。肿瘤细胞活力以及炎症细胞、基质细胞和血管细胞发生变化 将测量肿瘤微环境中的功能。我们将鉴定 PI4KIIIβ 依赖性分泌 介导这些变化的蛋白质并阐明它们如何发挥这些功能。我们的研究结果将提供 深入了解癌症中频繁扩增的染色体区域如何激活分泌过程 维持肿瘤细胞活力并影响肿瘤微环境中的多种过程。 总之，这里提供的证据将恶性分泌物与染色体区域联系起来，该区域是 在 KMLC 中经常被扩增，并为开发 PI4KIIIβ 拮抗剂作为首选的临床研究提供了基础 恶性分泌物的同类抑制剂。我们的研究结果阐明了恶性疾病的分子基础 分泌并表明染色体 1q 扩增的癌症很容易受到分泌阻断的影响。