PI 3 Kinase and Metastasis

PI 3 激酶和转移

• 批准号: 7534106
• 负责人: Jonathan M. Backer
• 金额: $ 23.35万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534106
• 关键词: 1-Phosphatidylinositol 3-Kinase; Actins; Adjuvant; Affect; Animal Model; Basement membrane; Behavior; Biological Assay; Biology; Blood; CDK6-associated protein p18; Cancer Patient; Cells; Chemotactic Factors; Chemotaxis; Class; Code; Collection; Data; Dependence; Development; Distant; Drug Delivery Systems; Epithelial; Exposure to; Extravasation; Figs - dietary; Funding; Gene Expression; Genes; Genetic; Hot Spot; Human; Image; In Vitro; Invaded; Invasive; Knock-in Mouse; Lead; Life; Lung; Mammary Neoplasms; Mammary gland; Measures; Mediating; Methods; Molecular Profiling; Motor; Mus; Mutate; Mutation; Myosin ATPase; Neoplasm Metastasis; Nonmuscle Myosin Type IIA; Oncogenic; PTEN gene; Paracrine Communication; Pathway interactions; Pattern; Phosphorylation; Phosphorylation Site; Phosphotransferases; Primary Neoplasm; Progress Reports; Property; Protein Isoforms; Protein Overexpression; Proteins; Publishing; Regulation; Regulatory Pathway; Resistance; Role; Signal Pathway; Signal Transduction; Site; Testing; Tetanus Helper Peptide; Transgenic Organisms; Tumor Cell Invasion; Work; Wound Healing; base; cell motility; cell type; cytokine; falls; genetic regulatory protein; in vivo; inhibitor/antagonist; insight; macrophage; malignant breast neoplasm; migration; mortality; mutant; neoplastic cell; novel; paracrine; programs; tumor; tumor progression; tumor xenograft

Metastatic tumor cells are distinguished by their ability to invade the basement membrane of epithelial barriers and migrate to distant sites. Recent studies from this program demonstrate that host macrophages are critical for the motility and invasion of tumor cells, due to a paracrine loop involving the mutual signaling and chemotaxis between macrophages and tumor cells. PI3K is a critical regulator of cell motility, and distinct PI3K isoforms are required for regulation of actin-based motility in tumor cells versus macrophages. We propose to use isoform-specific inhibitors of Class IA PISKs as well as genetic approaches to examine the requirement for PI3K-mediated motility of both tumor cells and macrophages during invasion and metastasis. By selectively inhibiting the motility of tumor cells versus macrophages, we will test whether the enhanced tumor cell chemotaxis observed in the presence of macrophages requires pre-exposure to macrophage-derived cytokines, versus the presence of continuous macrophage signaling during coordinated migration of the two cell types. We will also examine the metastatic behavior of tumor cells expressing activating mutations of PI3K that are commonly found in human breast cancer. The unique assays developed by this program will allow a detailed analysis of how oncogenic p110ct mutants affect the tumor cell-macrophage paracrine loop. Finally, studies from this program have shown that genes coding for proteins that modulate the myosin-ll regulatory pathway are up-regulated in invasive tumor cells and that the amoeboid motility of tumor cells in a 3D matrix is mediated by the myosin-ll regulatory pathway. Given these findings, and our observations that PI3K regulates myosin-ll-based contractility in tumor cells, we will examine the PI3K isoform-dependence of myosin-ll phosphorylation, the identification of intermediary signaling pathways in tumor cells and macrophages, and the subsequent effects on motility and invasion. These studies will complete our analysis of the motility cycle as it relates to the invasion signature, and lead to new insights into the role of macrophage-tumor cell paracrine signaling during metastasis.

转移性肿瘤细胞的特征在于其侵入上皮细胞基底膜的能力 障碍并迁移到遥远的地方。该计划的最新研究表明，宿主巨噬细胞 由于涉及相互信号传导的旁分泌环，对于肿瘤细胞的运动和侵袭至关重要 以及巨噬细胞和肿瘤细胞之间的趋化作用。 PI3K 是细胞运动的关键调节因子，并且 肿瘤细胞与巨噬细胞中基于肌动蛋白的运动的调节需要不同的 PI3K 亚型。 我们建议使用 IA 类 PISK 的异构体特异性抑制剂以及遗传方法来检查 肿瘤细胞和巨噬细胞在侵袭和迁移过程中对 PI3K 介导的运动的需求 转移。通过选择性抑制肿瘤细胞相对于巨噬细胞的运动，我们将测试是否 在巨噬细胞存在的情况下观察到的肿瘤细胞趋化性增强需要预先暴露于 巨噬细胞衍生的细胞因子，与协调过程中连续巨噬细胞信号传导的存在 两种细胞类型的迁移。我们还将检查表达肿瘤细胞的转移行为 激活人类乳腺癌中常见的 PI3K 突变。独特的分析 该计划开发的产品将能够详细分析致癌 p110ct 突变体如何影响肿瘤 细胞-巨噬细胞旁分泌环。最后，该计划的研究表明，编码 调节肌球蛋白-II 调节途径的蛋白质在侵袭性肿瘤细胞中上调，并且 3D 矩阵中肿瘤细胞的变形虫运动由肌球蛋白-II 调节途径介导。鉴于这些 研究结果以及我们观察到的 PI3K 调节肿瘤细胞中基于肌球蛋白 II 的收缩性，我们将 检查肌球蛋白-II 磷酸化的 PI3K 同工型依赖性，中间体的鉴定 肿瘤细胞和巨噬细胞中的信号通路，以及随后对运动和侵袭的影响。 这些研究将完成我们对运动周期的分析，因为它与入侵特征相关，并导致 对巨噬细胞-肿瘤细胞旁分泌信号在转移过程中的作用有新的见解。