Platelet PI3Kbeta regulation of metastasis

血小板 PI3Kbeta 对转移的调节

基本信息

批准号：
10645152
负责人：
Ryan C Graff
金额：
$ 5.27万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645152
关键词：
Adhesions Animals Antibodies Antineoplastic Agents Arteries Binding Biological Biosensor Blood Blood Circulation Blood Platelets Breast Cancer Cell Breast Carcinoma Breast Epithelial Cells Breast cancer metastasis Cancer Patient Cause of Death Cell Communication Cells Collagen Complex Data Distant Endothelium Epithelium Extravasation Fibrin Fibrinolytic Agents Genetic Transcription Hemorrhage Hemostatic function Human In Vitro Injections Intravenous Invaded Knock-in Label Leukocytes LoxP-flanked allele Lung MCF10A cells Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Measures Mediating Mediator Megakaryocytes Mesenchymal Morbidity - disease rate Mus Mutant Strains Mice NF-kappa B Neoplasm Circulating Cells Neoplasm Metastasis Occlusion injury PF4 Gene PIK3CG gene PTEN gene Patients Peptides Phenotype Phosphatidylinositols Phosphotransferases Platelet Activation Property Protein Isoforms Regulation Role Signal Transduction Site Solid Neoplasm Stromal Cells Testing Thrombin Thrombocytopenia Thrombus Time Transcriptional Activation Tumor Cell Invasion Tumor Cell Line Western Blotting Wild Type Mouse Work cancer type chemokine cytokine defined contribution experimental study immune clearance in vivo inhibitor matrigel migration mortality mutant neoplastic cell platelet function prevent promoter response stemness thrombotic transcriptome sequencing tumor wortmannin

项目摘要

Abstract Metastasis is the primary cause of morbidity and mortality among patients with solid tumors. Platelets interact with tumor cells upon their entry into the vasculature and promote the metastatic spread of these cells by several mechanisms. Circulating tumor cells (CTCs) directly bind to and activate platelets resulting in the formation of platelet-fibrin complexes that envelope circulating tumor cells and protect them from immune clearance. Adhesion to tumor cells also induces the release of platelet cytokines and other soluble factors that promote epithelial-mesenchymal transition in the tumor cells. Finally, platelets promote the adhesion of CTCs to the endothelium, assisting in their extravasation at distant metastatic sites. Platelet activation, adhesion, and in vivo thrombus formation require the activity of the Class IA PI 3-kinase PI3Kb. This isoform of PI3K produces the majority of PIP3 in platelets, suggesting that PI3Kb has a unique role in classical platelet activation. However, the role of PI3Kb in platelet-mediated cancer metastasis has yet to be defined. We propose that PI3Kb is required for platelet activation upon interaction with tumor cells, and thereby contributes to platelet-stimulated tumor metastasis. Aim 1 will test the role of platelet PI3Kb in platelet-stimulated tumor cell Matrigel invasion, transendothelial migration, epithelial-mesenchymal transition, cell stemness, NFkB activation, and platelet TGFb secretion. We will also use RNAseq and antibody arrays to more broadly examine the role of PI3Kb in platelet chemokine/cytokine release and in transcriptional responses by tumor cells. We will use both platelets from mice expressing mutant PI3Kb and human platelets pre-treated with the irreversible pan- PI3K inhibitor wortmannin. Aim 2 will directly evaluate the role of platelet PI3Kb in cancer metastasis in wild type and whole-animal or platelet-specific mutant PI3Kb mice. Murine mammary carcinoma cells will be injected intravenously to analyze in vivo tumor cell-platelet complex formation as well as tumor cell interactions with other leukocytes. We will also test the role of PI3Kb in tumor cell-induced thrombocytopenia and experimental metastasis. Isoform selective PI3Kb inhibitors were originally developed to be used as anti-thrombotic agents, as they prevent thrombotic occlusion of injured arteries without increasing bleeding. More recently these inhibitors have also been explored as anti-cancer agents in the treatment of PTEN-deficient cancers. This proposal seeks to understand the potential for a broader application of these agents in cancer patients to inhibit platelet activity and prevent metastasis in a variety of cancer types.

抽象的转移是实体瘤患者发病和死亡的主要原因。血小板相互作用肿瘤细胞进入脉管系统后与肿瘤细胞结合，并通过多种方式促进这些细胞的转移扩散机制。循环肿瘤细胞 (CTC) 直接结合并激活血小板，从而形成血小板-纤维蛋白复合物包裹循环肿瘤细胞并保护它们免受免疫清除。与肿瘤细胞的粘附还会诱导血小板细胞因子和其他可溶性因子的释放，从而促进肿瘤细胞的上皮-间质转化。最后，血小板促进 CTC 与细胞的粘附。内皮细胞，协助其外渗至远处转移部位。血小板活化、粘附和体内血栓形成需要 IA 类 PI 3 激酶的活性 PI3Kb。血小板中的大部分 PIP3 均由 PI3K 亚型产生，表明 PI3Kb 具有独特的作用在经典的血小板激活中。然而，PI3Kb 在血小板介导的癌症转移中的作用尚未明确。定义的。我们认为 PI3Kb 是血小板与肿瘤细胞相互作用时活化所必需的，因此有助于血小板刺激的肿瘤转移。目标 1 将测试血小板 PI3Kb 在血小板刺激中的作用肿瘤细胞基质胶侵袭、跨内皮迁移、上皮间质转化、细胞干性、NFkB 活化和血小板 TGFb 分泌。我们还将使用 RNAseq 和抗体阵列来更广泛地检查 PI3Kb 在血小板趋化因子/细胞因子释放和肿瘤细胞转录反应中的作用。我们将使用表达突变 PI3Kb 的小鼠血小板和经过不可逆泛-预处理的人血小板 PI3K 抑制剂渥曼青霉素。目标2将直接评估血小板PI3Kb在野生型癌症转移中的作用以及全动物或血小板特异性突变 PI3Kb 小鼠。将注射小鼠乳腺癌细胞静脉注射以分析体内肿瘤细胞-血小板复合物的形成以及肿瘤细胞与其他细胞的相互作用白细胞。我们还将测试 PI3Kb 在肿瘤细胞诱导的血小板减少症中的作用以及实验转移。同工型选择性 PI3Kb 抑制剂最初被开发用作抗血栓药物，因为它们防止受伤动脉血栓闭塞而不增加出血。最近这些抑制剂已也被探索作为治疗 PTEN 缺陷癌症的抗癌药物。该提案旨在了解这些药物在癌症患者中更广泛应用以抑制血小板活性的潜力并预防多种癌症类型的转移。