How does malignancy subvert platelet and megakaryocytic biology?

恶性肿瘤如何破坏血小板和巨核细胞生物学？

• 批准号: 10058814
• 负责人: Elisabeth M Battinelli
• 金额: $ 55.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-16 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058814
• 关键词: Address; Advanced Malignant Neoplasm; Alpha Granule; Applications Grants; Automobile Driving; Back; Biological; Biology; Blood; Blood Platelets; Breast Cancer Cell; Breast Cancer Patient; Cancer Biology; Cardiovascular Diseases; Cell Communication; Cell Nucleus; Cells; Charge; Clinical; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Foundations; Growth; Hemostatic function; Immunologic Surveillance; Individual; Investigation; Laboratories; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Megakaryocytes; Messenger RNA; Methods; Modality; Molecular; Mothers; Neoplasm Metastasis; Organogenesis; Pathway interactions; Patients; Phase; Phenotype; Platelet Activation; Platelet Count measurement; Play; Production; Prognosis; Property; Protein Biosynthesis; Proteins; Publications; RANTES; Role; Sampling; Signal Pathway; Therapeutic Intervention; Time; Translating; Tumor Cell Invasion; Up-Regulation; Work; chemokine; clinically significant; experience; improved; innovation; malignant breast neoplasm; malignant phenotype; neoplastic cell; neovascularization; novel; novel therapeutics; platelet phenotype; polysome profiling; response; stem cells; targeted treatment; thrombocytosis; translational study; tumor; tumor growth; tumor progression; uptake

Project Summary Traditionally viewed as the bandaids of the blood, the contribution of platelets to the progression of malignancy is emerging as a compelling focus for therapeutic intervention. Complex interactions between tumor cells, and circulating platelets play an important role in tumor growth and dissemination, and a growing body of data supports a role for platelet activation and release of chemokines in metastases and neovascularization. Supporting this concept is the evidence that elevated platelet counts (thrombocytosis) at time of diagnosis with malignancy is a harbinger of an aggressive cancer with a poor prognosis. One very interesting and provocative connection between cancer and platelets is the increasing evidence that tumor cells hijack platelets to promote a more pro-malignant phenotype to drive disease progression. Our laboratories have been instrumental in establishing the pro-malignant role of platelets in metastasis and neovascularization. We have recently discovered that tumor cells can instruct platelets to release CCL5, a known driver of tumor cell invasion and metastasis, and have expanded the role of CCL5 not only as a regulator of metastasis but also as a central controller of platelet production. Despite this progress, how tumor cells instruct megakaryocytes to increase platelet production, and how malignancy reprograms megakaryocytes and manipulates platelet phenotype to support tumor growth and metastasis remains an enigma. Since platelets play a central role in driving cancer, this proposal will address three interrelated while independent Specific Aims focused on the cell biological and molecular pathways by which tumor cells hijack megakaryocytes and platelets to promote cancer growth. Specific Aim 1 will determine the role of the chemokine CCL5 as a major driver of thrombocytosis in malignancy via upregulation of megakaryocyte maturation and proplatelet production. Specific Aim 2 will determine how malignancy reprograms megakaryocytes to produce a more pro-malignant platelet phenotype, with upregulation of factors essential to neovascularization and metastasis. Specific Aim 3 will determine the clinical significance of CCL5 driven platelet production and megakaryocyte reprogramming by elucidating the impact of each in breast cancer patients. This work is innovative because it enters unchartered territory and takes a multifaceted experimental approach to understanding how tumor cells hijack platelets by uniting work on platelet production with cancer biology. Taken together, we expect that this investigation will demonstrate the molecular mechanisms by which malignancy can subvert normal platelet biology by manipulating the megakaryocyte to promote cancer growth and metastasis, and lay the foundation for the development of novel therapeutic modalities.

项目摘要 传统上被视为血液的创可贴，血小板对恶性肿瘤的发展 正在成为治疗干预的引人注目的重点。肿瘤细胞之间的复杂相互作用， 循环血小板在肿瘤的生长和传播中起着重要作用，并且越来越多的数据体 支持在转移和新血管形成中趋化因子的血小板激活和释放的作用。 支持这一概念的证据表明，诊断时血小板计数升高（血小板病） 恶性肿瘤是预后不良的侵略性癌症的预兆。一个非常有趣和挑衅的 癌症与血小板之间的联系是越来越多的证据表明肿瘤细胞劫持血小板以促进 一种更启发疾病进展的更挑战的表型。我们的实验室在 建立血小板在转移和新血管形成中的促恶作用。我们最近有 发现肿瘤细胞可以指导血小板释放CCL5，这是肿瘤细胞侵袭和 转移，并扩大了CCL5的作用，不仅是转移的调节剂，而且还扩大了中心 血小板产生的控制器。尽管取得了进展，肿瘤细胞如何指示巨核细胞增加 血小板的产生以及恶性重编程如何进行巨核细胞并操纵血小板表型 支持肿瘤生长和转移仍然是一个谜。由于血小板在驱动癌症中起着核心作用，因此 该建议将解决三个相互关联的，而独立特定目的则集中于细胞生物学和 肿瘤细胞劫持巨核细胞和血小板以促进癌症生长的分子途径。 具体目标1将确定趋化因子CCL5作为血小板病的主要驱动力的作用 通过上调巨核细胞成熟和预言产生的恶性肿瘤。具体目标2将 确定恶性重编程巨核细胞如何产生更恶性的血小板表型， 随着新生血管形成和转移必不可少的因素的上调。特定目标3将确定 CCL5驱动的血小板产生和巨核细胞重新编程的临床意义通过阐明 每个人在乳腺癌患者中的影响。这项工作具有创新性，因为它进入了未经封面的领土和 采用多方面的实验方法来理解肿瘤细胞如何通过团结工作来劫持血小板 与癌症生物学产生血小板。综上所述，我们希望这项调查将证明 恶性肿瘤可以通过操纵正常血小板生物学的分子机制 巨核细胞以促进癌症的生长和转移，并为发展的发展奠定了基础 治疗方式。

项目成果

Platelets upregulate tumor cell programmed death ligand 1 in an epidermal growth factor receptor-dependent manner in vitro.

• DOI: 10.1182/bloodadvances.2021006120
• 发表时间: 2022-10-25
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Guo, Qiuchen;Malloy, Michael W.;Roweth, Harvey G.;McAllister, Sandra S.;Italiano, Joseph E.;Battinelli, Elisabeth M.
• 通讯作者: Battinelli, Elisabeth M.

Pro-inflammatory megakaryocyte gene expression in murine models of breast cancer.

• DOI: 10.1126/sciadv.abo5224
• 发表时间: 2022-10-14
• 期刊: Science advances
• 影响因子: 13.6

Lessons to learn from tumor-educated platelets.

• DOI: 10.1182/blood.2019003976
• 发表时间: 2021-06-10
• 期刊: Blood
• 影响因子: 20.3
• 作者: Roweth HG;Battinelli EM
• 通讯作者: Battinelli EM

Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis.

• DOI: 10.1161/atvbaha.116.308791
• 发表时间: 2017-04
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Johnson KE;Forward JA;Tippy MD;Ceglowski JR;El-Husayni S;Kulenthirarajan R;Machlus KR;Mayer EL;Italiano JE Jr;Battinelli EM
• 通讯作者: Battinelli EM