Platelet PI3Kbeta regulation of metastasis

血小板 PI3Kbeta 对转移的调节

基本信息

批准号：
10315108
负责人：
Ryan C Graff
金额：
$ 5.1万
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/10315108
关键词：
1-Phosphatidylinositol 3-Kinase 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 Epithelial Extravasation Fibrin Fibrinolytic Agents Genetic Transcription Hemorrhage Hemostatic function Human In Vitro Injections Intravenous Knock-in Label Leukocytes LoxP-flanked allele Lung MCF10A cells Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Measures Mediating Mediator of activation protein Megakaryocytes Mesenchymal Morbidity - disease rate Mus Mutant Strains Mice Neoplasm Circulating Cells Neoplasm Metastasis Occlusion injury PF4 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 Transitional Cell 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/antagonist 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率和死亡率的主要原因。血小板相互作用肿瘤细胞进入脉管系统时，并通过几个细胞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，导致形成血小板 - 纤维蛋白复合物包膜循环肿瘤细胞并保护其免疫清除率。对肿瘤细胞的粘附还诱导血小板细胞因子和其他可溶性因子的释放肿瘤细胞中的上皮间质转变。最后，血小板促进了CTC对内皮，协助在远处转移部位进行渗出。血小板激活，粘附和体内血栓形成需要IA PI 3-激酶的活性 PI3KB。 PI3K的这种同工型在血小板中产生大部分PIP3，这表明PI3KB具有独特的作用在经典血小板激活中。但是，PI3KB在血小板介导的癌症转移中的作用尚未是定义。我们提出，与肿瘤细胞相互作用后，PI3KB是血小板激活所必需的，从而有助于血小板刺激的肿瘤转移。 AIM 1将测试血小板PI3KB在血小板刺激中的作用肿瘤细胞矩阵侵袭，跨内皮迁移，上皮 - 间质转变，细胞干，NFKB 激活和血小板TGFB分泌。我们还将使用RNASEQ和抗体阵列进行更广泛的检查 PI3KB在血小板趋化因子/细胞因子释放以及肿瘤细胞转录反应中的作用。我们将使用表达突变体PI3KB的小鼠和人血小板的小鼠，并用不可逆的泛池进行治疗 PI3K抑制剂磨牙。 AIM 2将直接评估血小板PI3KB在癌症转移中的作用以及全动物或血小板特异性突变体PI3KB小鼠。将注射鼠类乳腺癌细胞静脉注射分析体内肿瘤细胞 - 血小板复合物以及肿瘤细胞与其他的相互作用白细胞。我们还将测试PI3KB在肿瘤细胞诱导的血小板减少症和实验性的作用转移。同工型选择性PI3KB抑制剂最初被开发为用作抗栓性药物防止血栓闭塞受伤的动脉，而不会增加出血。最近，这些抑制剂具有在治疗缺陷型癌症方面，也被探讨为抗癌药。该提议试图了解这些药物在癌症患者中更广泛应用抑制血小板活性的可能性并防止各种癌症类型的转移。