Platelet PI3Kbeta regulation of metastasis

血小板 PI3Kbeta 对转移的调节

• 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
• 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

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.

摘要 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 与肿瘤细胞进入血管系统，并促进这些细胞的转移性扩散 机制。循环中的肿瘤细胞(CTCs)直接与血小板结合并激活，从而形成 血小板-纤维蛋白复合体，包裹循环中的肿瘤细胞，保护它们免受免疫清除。 与肿瘤细胞的黏附也会诱导血小板细胞因子和其他促进 肿瘤细胞的上皮间充质转化。最后，血小板促进CTCs与 血管内皮细胞，协助它们在远处转移部位的外渗。 血小板的激活、黏附和体内血栓的形成需要IA类PI 3-激酶的活性 PI3Kb。PI3K的这种异构体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不清楚。 已定义。我们认为，PI3Kb是血小板与肿瘤细胞相互作用时激活所必需的，因此 促进了血小板刺激的肿瘤转移。目的1检测血小板PI3Kb在血小板刺激中的作用 肿瘤细胞基质侵袭、跨内皮细胞迁移、上皮-间充质转化、细胞干性、NFkB 活化和血小板TGFb的分泌。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会 用表达突变型PI3Kb的小鼠血小板和经不可逆PAN处理的人血小板. PI3K抑制剂Wortmannin。目的2直接评价血小板PI3Kb在野生型肿瘤转移中的作用 以及全动物或血小板特异性突变的PI3Kb小鼠。小鼠乳腺癌细胞将被注射 静脉注射分析体内肿瘤细胞-血小板复合体的形成以及肿瘤细胞与其他 白细胞。我们还将测试PI3Kb在肿瘤细胞诱导的血小板减少中的作用和实验性 转移。 异构体选择性PI3Kb抑制剂最初是为了用作抗血栓药物而开发的，因为它们 在不增加出血的情况下防止损伤动脉的血栓闭塞。最近，这些抑制剂已经 还被探索作为抗癌剂用于治疗PTEN缺陷性癌症。这项建议旨在 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可能性 并防止各种癌症类型的转移。