Platelets in Cancer

癌症中的血小板

• 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
• 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

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.

摘要 该提案的中心是癌症相关血栓形成的机制，也称为 特鲁索综合征。在许多癌症中，血小板介导的血栓形成是导致癌症的主要原因。 发病率血小板以高于任何其他细胞的水平存在于血液中，它们的活化和 聚集导致血栓形成。由于存在大量的储存颗粒， 能够吸收一些重要的介质。我们的几个实验证据， 其他研究小组认为，肿瘤的存在改变了血小板转录组、分泌组（储存 颗粒含量）以及血小板活化状态，从而产生所谓的“受肿瘤训练的血小板”。 我们已经证明，来自荷瘤小鼠的血小板和来自癌症患者的血小板不携带 不仅蛋白质或肿瘤来源，而且肿瘤特异性RNA。为了了解肿瘤RNA如何找到它们的 在研究血小板的过程中，我们关注的是由侵袭性肿瘤产生的称为外泌体的囊泡 并含有肿瘤特异性RNA和蛋白质。我们证明了肿瘤外泌体可以有效地 在体外和体内被血小板摄入，导致血小板转录组和血小板的变化 activation.利用这些初步结果，我们假设肿瘤外泌体，含有 肿瘤信号，通过CD 63和血小板分泌颗粒被血小板有效吸收 机械（VAMP）。这导致血小板转录组的变化，并最终导致血小板 过度活化导致血栓形成。AIM 1.为了确定外泌体摄取的机制， 血小板使用来自前列腺癌细胞和患者的exo，我们将评估CD 63的作用， 其在体外和体内血小板外摄取中的糖基化。血小板的作用 将使用VAMP 8、VAMP 3、Arf 6 KO测试外泌体摄取中的内吞/胞吐机制 血小板目标2.明确外源性血小板激活的体内机制， 干预的目标。将在研究中监测肿瘤和肿瘤衍生的exo引起的血小板活化。 体内存在或不存在CD 63阻断试剂。AIM3.为了定义肿瘤特异性签名， 从癌症患者的血液中分离的外源血小板和循环血小板。我们将重点关注前列腺 癌症患者，并将测量外泌体和血小板中选定的肿瘤特异性标志物， qPCR。将对患者在动脉瘤切除术前、术后3个月和6个月的血小板进行测定， 肿瘤特异性报告基因和激活状态。这些研究旨在确定特定的 肿瘤外泌体激活血小板的机制和后果，并开发新的 干预癌症相关血栓形成的治疗策略。

项目成果

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.)
• 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)
• 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

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

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