Platelets in Cancer

癌症中的血小板

基本信息

批准号：
10199008
负责人：
Tatiana V Byzova
金额：
$ 66.33万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199008
关键词：
Address Affect Agonist Animal Model Antibodies Apolipoprotein E Binding Biological Assay Biology Blood Blood Platelets Bone Marrow Cancer Patient Cardiovascular system Cells Clinical Research Communication Cytoplasmic Granules Data Dose Endocytosis Event Excision Exocytosis Experimental Models Growth Factor Hematopoietic Neoplasms Hyperactivity In Vitro Intake Intervention Kinetics Label Life Longevity Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Mediator of activation protein Messenger RNA Molecular Monitor Morbidity - disease rate Mus Myeloid Cells Neoplasm Metastasis Nested PCR P-Selectin PSA level Patients Platelet Activation Prostatectomy Proteins RNA Reagent Reporter Reporting Research Risk Role Secretory Vesicles Study models Syndrome Testing Thrombin Thromboembolism Thrombosis Tissues Tumor Angiogenesis Tumor Biology Tumor-Derived Untranslated RNA Validation Vesicle anti-cancer therapeutic base bone cancer site cellubrevin cohort cytokine design exosome experience extracellular vesicles glycosylation human subject implantation improved in vivo mortality novel novel therapeutic intervention platelet function prevent prostate cancer cell recruit repository side effect therapeutic target transcriptome transcriptome sequencing tumor tumor growth uptake vesicle-associated membrane protein

项目摘要

Abstract This proposal centers on the mechanisms of cancer-associated thrombosis, also known as Trousseau's syndrome. In many cancers, platelet-mediated thrombosis is the leading cause of morbidity. Platelets are present in blood at levels higher than any other cell and their activation and aggregation leads to thrombosis. Due to the presence of numerous storage granules, platelets are able to uptake a number of important mediators. Several lines of experimental evidence from our and other groups suggest that the presence of tumor changes platelet transcriptome, secretome (storage granules content) as well as platelet activation status resulting in so-called “tumor-educated platelets”. We have shown that platelets from tumor-bearing mice and platelets from cancer patients carry not only proteins or tumor origin but also tumor-specific RNAs. To understand how tumor RNAs find their way to platelets, we focus on vesicles called exosomes, which are produced by aggressive tumors and contain tumor-specific RNAs and proteins. We demonstrated that tumor exosomes are efficiently taken in by platelets in vitro and in vivo, resulting in changes of platelet transcriptome and platelet activation. Capitalizing on these preliminary results we hypothesized that tumor exosomes, containing tumor signature, are efficiently taken in by platelets via CD63 and platelet secretory granules machinery (VAMPs). This results in changes in platelet transcriptome and, eventually, in platelet hyperactivation leading to thrombosis. AIM1. To determine the mechanisms of exosome uptake by platelets. Using exo from prostate cancer cells and from patients, we will assess the role of CD63 and its glycosylation in exo uptake by platelets in vitro and in vivo. The role of platelet endocytosis/exocytosis machinery in exosomes uptake will be tested using VAMP8, VAMP3, Arf6 KO platelets. AIM2. To define the mechanisms of platelet activation by exo in vivo and identify potential targets for intervention. Platelet activation by tumors and tumor-derived exo will be monitored in the presence or absence of CD63 blocking reagents in vivo. AIM3. To define tumor-specific signature in both, exo and circulating platelets isolated from blood of cancer patients. We will focus on prostate cancer patients and will measure selected tumor-specific markers in exosomes and platelets by qPCR. Platelets from patients before and 3 and 6 months after prostatectomy will be assayed for tumor-specific reporters and activation status. These studies are designed to define the specific mechanisms and consequences of platelets activation by tumor exosomes and develop new therapeutic strategies to interfere with cancer-associated thrombosis.

抽象的该提议集中于与癌症相关血栓形成的机制，也称为特鲁索综合症。在许多癌症中，血小板介导的血栓形成是发病率。血小板以高于任何其他细胞的血液中存在，及其激活以及它们的激活和聚集导致血栓形成。由于存在许多存储颗粒，血小板是可以吸引许多重要的调解人。来自我们和的几条实验证据其他小组表明，肿瘤的存在改变了血小板转录组，分泌组（存储）颗粒含量）以及血小板激活状态，导致所谓的“受过肿瘤教育的血小板”。我们已经表明，来自肿瘤的小鼠和癌症患者血小板的血小板不带仅蛋白质或肿瘤起源，但肿瘤特异性RNA。了解肿瘤RNA如何找到他们的到血小板的方式，我们专注于称为外泌体的蔬菜，这些蔬菜是由侵略性肿瘤产生的并包含肿瘤特异性RNA和蛋白质。我们证明了肿瘤外泌体有效在体外和体内通过血小板吸收，导致血小板转录组和血小板变化激活。利用这些初步结果，我们假设肿瘤外泌体包含肿瘤特征通过CD63和血小板分泌颗粒有效地吸收肿瘤特征机械（鞋面）。这会导致血小板转录组的变化，并最终在血小板中变化过度激活导致血栓形成。 AIM1。确定由血小板。使用前列腺癌细胞和患者的EXO，我们将评估CD63和血小板在体外和体内摄取EXO摄取中的糖基化。血小板的作用外泌体摄取中的内吞和胞吐作用机制将使用VAMP8，VAMP3，ARF6 KO进行测试血小板。 AIM2。通过体内EXO定义血小板激活的机制并识别潜力干预的目标。肿瘤和肿瘤衍生的EXO的血小板激活将受到监测在体内存在CD63阻断试剂的存在或不存在。 AIM3。定义肿瘤特异性签名从癌症患者血液中分离出的EXO和循环血小板。我们将专注于前列腺癌症患者，将测量外泌体和血小板中选定的肿瘤特异性标记 qpcr。将分配前列腺切除术后患者的血小板和6个月后肿瘤特异性记者和激活状态。这些研究旨在定义特定肿瘤外泌体激活血小板的机制和后果并发展了新的干扰癌症相关血栓形成的治疗策略。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Remodeling vasculature to avoid blindness.

重塑脉管系统以避免失明。

DOI：
10.1126/science.abd7063
发表时间：
2020
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Podrez,EugeneA;Byzova,TatianaV
通讯作者：
Byzova,TatianaV

Macrophage Migration and Phagocytosis Are Controlled by Kindlin-3's Link to the Cytoskeleton.

DOI：
10.4049/jimmunol.1901134
发表时间：
2020-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Liu H;Zhu L;Dudiki T;Gabanic B;Good L;Podrez EA;Cherepanova OA;Qin J;Byzova TV
通讯作者：
Byzova TV

Circulating CD36 is increased in hyperlipidemic mice: Cellular sources and triggers of release.

DOI：
10.1016/j.freeradbiomed.2021.03.004
发表时间：
2021-05-20
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Biswas S;Gao D;Altemus JB;Rekhi UR;Chang E;Febbraio M;Byzova TV;Podrez EA
通讯作者：
Podrez EA

Kindlin-3 mutation in mesenchymal stem cells results in enhanced chondrogenesis.

DOI：
10.1016/j.yexcr.2020.112456
发表时间：
2021-02-15
期刊：
Experimental cell research
影响因子：
3.7
作者：
Kerr BA;Shi L;Jinnah AH;Harris KS;Willey JS;Lennon DP;Caplan AI;Byzova TV
通讯作者：
Byzova TV

Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.

DOI：
10.1016/j.bone.2022.116397
发表时间：
2022-07
期刊：
BONE
影响因子：
4.1
作者：
Dudiki, Tejasvi;Nascimento, Daniel W.;Childs, Lauren S.;Kareti, Swetha;Androjna, Charlie;Zhevlakova, Irina;Byzova, Tatiana, V
通讯作者：
Byzova, Tatiana, V