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Platelet PI3Kbeta regulation of metastasis

血小板 PI3Kbeta 对转移的调节

基本信息

批准号：
10437636
负责人：
Ryan C Graff
金额：
$ 5.18万
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/10437636
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 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.

摘要