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

KRAS突变型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 并在此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，这一过程下文称为 “恶性分泌物”。阻断恶性分泌物的治疗策略尚未开发。 我们已经确定了一个染色体1 q扩增子窝藏和许多调节囊泡生物发生 和运输，包括磷脂酰肌醇4-激酶IIIβ（PI 4KIII β），一种高尔基体专用激酶， 磷脂酰肌醇4-磷酸（PI 4P）。我们发现， 1 q扩增的KMLC细胞需要PI 4KIII β。选择性PI 4KIII β拮抗剂优先诱导细胞凋亡， 抑制1 q扩增的KMLC细胞的转移特性。基于这些发现，我们假设 高PI 4KIII β水平促进KMLC生长和转移，并赋予对PI 4KIII β拮抗剂的脆弱性。 为了验证这一假设，我们在目的1中提出了一种表达PI 4KIII β的本地KMLC模型， 确定PI 4KIII β是否增强KMLC转移倾向并赋予对PI 4KIII β的易感性 对手。我们的研究结果将阐明PI 4KIII β驱动KMLC进展的方式，并可能提供一种新的治疗方法。 为使用PI 4KIII β拮抗剂的新治疗方法奠定了基础。 我们发现在1 q扩增的KMLC细胞中高水平的PI 4KIII β增强了顺行囊泡运输， 并刺激促存活和促转移因子的分泌。PI 4KIII β驱动的转移特性 需要高尔基体磷蛋白3（GOLPH 3），一种PI 4P-束缚的高尔基体蛋白，促进囊泡出芽， 高尔基体网络。因此，我们假设PI 4KIII β依赖性分泌是激活前体细胞所必需的。 在肿瘤微环境中的转移过程，并维持1 q扩增的KMLC细胞的活力。到 为了验证这一假设，我们将在表达PI 4KIII β的本地KMLC中表达Golph 3，并在1 q扩增的 原位KMLC。肿瘤细胞活力和炎性、基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PI 4KIII β依赖性分泌的 蛋白质介导这些变化，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，这里提出的证据将恶性分泌物与染色体区域联系起来， 在KMLC中经常扩增，并为临床研究提供了基础，以开发PI 4KIII β拮抗剂作为第一个 恶性分泌物的同类抑制剂。我们的发现阐明了恶性肿瘤的分子基础 分泌，并显示染色体1 q扩增的癌症易受分泌阻断的影响。

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.