Tissue factor regulation of receptor tyrosine kinases in glioblastoma

胶质母细胞瘤中受体酪氨酸激酶的组织因子调节

• 批准号: 10651723
• 负责人: Michael Raymond Drumm
• 金额: $ 5.27万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651723
• 关键词: Adult; Attenuated; Behavior; Binding; Blood coagulation; Brain; Cell Proliferation; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Coupled; Data; Disease; Engraftment; Epidermal Growth Factor Receptor; G-Protein-Coupled Receptors; Genes; Genetic; Glioblastoma; Glioma; Goals; Growth; Immunocompetent; Immunoprecipitation; Immunosuppression; Investigation; KDR gene; Knock-out; Literature; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; Molecular; Mus; Myeloid Cells; PAR-2 Receptor; Pathway interactions; Patient Care; Patients; Phenotype; Process; Proliferating; Protease Inhibitor; Proteins; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recurrent tumor; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; T-Cell Proliferation; Testing; Therapeutic; Thromboplastin; Tissues; Tumor Immunity; Tumor-infiltrating immune cells; Tumorigenicity; Tyrosine Kinase Receptor Inhibition; Western Blotting; Work; angiogenesis; cancer stem cell; improved; in vitro Assay; in vivo; migration; monocyte; new therapeutic target; pharmacologic; programmed cell death ligand 1; receptor; self-renewal; stem cell biomarkers; stem cell population; success; tumor microenvironment; tumor-immune system interactions; wound healing

Project Summary Glioblastoma (GBM) is the most common cancer arising in the adult brain, yet despite years of intensive research, it remains a fatal disease. Major barriers to improving GBM treatment include the cancer stem cell (CSC) phenotype, a self-renewing behavior that facilitates tumor recurrence and therapy resistance, and the profoundly immunosuppressive microenvironment of GBM. Activation of receptor tyrosine kinases (RTKs) is implicated in both of these processes. A better understanding of what triggers RTK signaling, and how it leads to the CSC phenotype and immunosuppression in GBM, is essential for improving patient care. Our preliminary and published data have established the importance of Tissue Factor (TF) in GBM malignancy. TF is a protein involved in blood clotting, but it can also bind and activate protease-activated receptor 2 (PAR2), a transmembrane G protein-coupled receptor that promotes cell proliferation, migration, and angiogenesis. This TF-induced process exists to facilitate wound healing, but can be harnessed by cancers to increase their malignancy. In many cancers, including glioma, high TF expression correlates with worse patient survival, and our recently published work demonstrated that suppression of TF greatly attenuates the aggressiveness of GBM. In our preliminary and published data, we found that TF is an upstream activator of multiple classes of RTKs, including class I (EGFR), II (IGF-IR), III (PDGFRβ), IV (VEGFR-2), and X (Axl). We also found that TF acts through an intracellular pathway to do so, and that TF is a major contributor to the CSC phenotype in GBM. Furthermore, we found that TF can upregulate the expression of PD-L1, which is a protein found on GBM and myeloid cells that when bound can suppress antitumor immunity by inhibiting the activity and proliferation of T cells. However, the mechanisms whereby TF exerts these effects in GBM are still unclear. Our overarching hypothesis is that TF promotes CSC subpopulations, and suppresses antitumor immunity, through PAR2- mediated activation of the intracellular domain of RTKs. In the first Specific Aim of the proposal, we will investigate the mechanisms by which TF stimulates RTK signaling by determining what constitutes the binding partner complex that activates RTKs, and by examining the detailed role of TF and PAR2 in RTK activation. The second Specific Aim will focus on the role that TF-mediated RTK activation has on the CSC phenotype in GBM. The third Specific Aim will investigate the role of TF-PAR2-RTK signaling in immunosuppression in GBM, and if therapeutics can inhibit this process and prolong survival of mice. The long-term goals of the proposed work are to improve the understanding of how TF promotes malignant behavior, elucidate a new mechanism by which RTKs are activated in cancer, and to demonstrate the therapeutic potential of blocking TF-PAR2 signaling.

项目摘要 胶质母细胞瘤（GBM）是成人大脑中最常见的癌症，尽管多年来对它进行了深入的研究， 研究表明，它仍然是一种致命的疾病。改善GBM治疗的主要障碍包括癌症干细胞 (CSC)表型，一种促进肿瘤复发和治疗抗性的自我更新行为， GBM免疫抑制微环境。受体酪氨酸激酶（RTK）的激活是 在这两个过程中都有牵连。更好地了解触发RTK信号的因素以及它如何导致 CSC表型和GBM中的免疫抑制，对于改善患者护理至关重要。我们的初步 和已发表的数据已经确立了组织因子（TF）在GBM恶性肿瘤中的重要性。TF是一种蛋白 参与血液凝固，但它也可以结合和激活蛋白酶激活受体2（PAR 2）， 跨膜G蛋白偶联受体，促进细胞增殖、迁移和血管生成。这 TF诱导的过程存在以促进伤口愈合，但可以被癌症利用以增加其 恶性肿瘤在包括神经胶质瘤在内的许多癌症中，高TF表达与患者生存率较差相关， 我们最近发表的工作表明，TF的抑制大大减弱了GBM的侵袭性。 在我们的初步和已发表的数据中，我们发现TF是多种RTK的上游激活剂， 包括I类（EGFR）、II类（IGF-IR）、III类（PDGFRβ）、IV类（VEGFR-2）和X类（Axl）。我们还发现TF的作用 通过细胞内途径这样做，TF是GBM中CSC表型的主要贡献者。 此外，我们发现TF可以上调PD-L1的表达，PD-L1是在GBM上发现的蛋白质， 骨髓细胞，当结合时，可以通过抑制T细胞的活性和增殖来抑制抗肿瘤免疫 细胞然而，TF在GBM中发挥这些作用的机制仍不清楚。我们的总体 一种假说认为TF通过PAR 2 - 1促进CSC亚群，并抑制抗肿瘤免疫。 介导的RTK胞内结构域的活化。在第一个具体目标中，我们将 研究TF刺激RTK信号传导的机制，通过确定什么构成了结合 伴侣复合物激活RTK，并通过检查详细的作用，TF和PAR 2在RTK激活。的 第二个具体目标将集中在TF介导的RTK激活对GBM中CSC表型的作用。 第三个具体目标将研究TF-PAR 2-RTK信号传导在GBM中的免疫抑制中的作用，如果 治疗剂可以抑制这一过程并延长小鼠的存活。拟议工作的长期目标是 为了提高对TF如何促进恶性行为的理解，阐明一种新的机制， RTKs在癌症中被激活，并证明阻断TF-PAR 2信号传导的治疗潜力。