Platelet Serine/Threonine Phosphatases in Cancer Pathophysiology

癌症病理生理学中的血小板丝氨酸/苏氨酸磷酸酶

• 批准号: 10360475
• 负责人: K. Vinod VIJAYAN
• 金额: $ 41.22万
• 依托单位: BAYLOR 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: 2021-03-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360475
• 关键词: Adjuvant; Anoikis; Apoptosis; Aspirin; Attenuated; Biogenesis; Biological Markers; Blood; Blood Platelets; Bone Marrow; CD8-Positive T-Lymphocytes; Cancer Biology; Cancer Patient; Cardiovascular Diseases; Catalytic Domain; Cause of Death; Cell Lineage; Cell Survival; Colon Carcinoma; Databases; Diagnostic; Disease; Disease Progression; Environment; Experimental Models; Extracellular Protein; Functional disorder; Growth; Growth Factor; Human; Immune; Immune Evasion; Immune response; Immunology; Intervention; LRRC32 gene; Lead; Ligands; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Megakaryocytes; Messenger RNA; Metastatic Neoplasm to the Lung; Methods; Mouse Protein; Mus; Neoplasm Metastasis; Patients; Phosphoric Monoester Hydrolases; Platelet Count measurement; Platelet Glycoproteins; Protein Kinase; Protein Phosphatase-1 alpha; Protein Serine/Threonine Phosphatase; Protein phosphatase; Proteins; Proteome; Proteomics; RNA; Research Personnel; Role; Serine; Signal Pathway; Signal Transduction; Site; Source; Stream; Supporting Cell; Survival Rate; T-Lymphocyte; Testing; The Cancer Genome Atlas; Therapeutic; Transcription Coactivator; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Treatment Efficacy; Tumor Burden; United States; Work; anti-melanoma immunity; anticancer research; base; cancer cell; cancer immunotherapy; cancer survival; chemotherapeutic agent; clopidogrel; exhaustion; extracellular; immune checkpoint; improved; in vivo; insight; lung cancer cell; mortality; mouse model; neoplastic cell; novel; novel strategies; prevent; programmed cell death ligand 1; programmed cell death protein 1; screening; thrombocytosis; tumor; tumor microenvironment; tumor progression

The five year survival rate for lung cancer is ~20% despite improved screening methods and advances in treatment. Tumor metastasis is one of the major causes of death in cancer patients. Besides the dysregulated signaling in tumor cells, the survival of dislodged circulating tumors from detachment-induced apoptosis (anoikis) and immune attack in the blood depends on a crosstalk between the tumor and support cells in the tumor microenvironment, including blood platelets. Lung cancer patients with high platelet count are often associated with worst survival and a lower efficacy towards chemotherapeutic agents. Although platelets are a determinant in tumor metastasis, current anti-platelet therapy (aspirin and clopidogrel) with an established role in cardiovascular disease, has challenges when deployed for the management of cancer. Therefore, new approaches to better understand the platelet-cancer crosstalk is needed to identify novel platelet targets. Interestingly, platelets from cancer subjects have quantitative changes in the proteome. It is currently unknown if the cancer-induced changes in platelet protein(s) merely serve as a biomarker(s) or promote disease progression. This critical unanswered problem in the field has the potential to provide new insights into disease mechanisms that are influenced by platelets. Recent studies suggest a role for the catalytic subunit of protein phosphatase 1 (PP1c) in the platelet-cancer crosstalk. Our preliminary studies revealed that the platelets isolated from human lung cancer patients and mice with experimental lung cancer show increased PP1cα protein compared to the non-cancer controls. Importantly, conditional deletion of PP1cα in platelets showed reduced tumor burden in an experimental model of lung cancer metastasis. Our overarching hypothesis is that platelet PP1cα facilitates lung cancer metastasis by reducing detachment-induced apoptosis (anoikis) and/or promoting an immunosuppressive milieu. This proposal will determine how platelet PP1cα promotes lung cancer metastasis using novel mice models and investigators with expertise in platelet phosphatases, cancer biology, platelet-cancer cross talk and immunology of lung cancer. In Aim 1, we will investigate the role of platelet PP1cα in lung cancer survival and metastasis. Aim 2 will determine the role of platelet PP1cα on immune responses to lung cancer. This work could lead to studies wherein simultaneous blockade of platelet/extracellular PP1cα along with immune check points may provide exclusive opportunities to optimize cancer immunotherapy.

尽管筛查方法有所改进且技术进步，但肺癌的五年生存率约为 20% 治疗。肿瘤转移是癌症患者死亡的主要原因之一。除了失调的 肿瘤细胞中的信号传导，脱离诱导的细胞凋亡而脱落的循环肿瘤的存活 （失巢凋亡）和血液中的免疫攻击取决于肿瘤和支持细胞之间的串扰 肿瘤微环境，包括血小板。血小板计数高的肺癌患者通常 与最差的生存率和化疗药物的较低疗效相关。虽然血小板是 肿瘤转移的决定因素，目前的抗血小板治疗（阿司匹林和氯吡格雷）具有确定的作用 在心血管疾病中，当用于癌症治疗时面临挑战。因此，新 需要更好地了解血小板-癌症串扰的方法来识别新的血小板靶标。 有趣的是，来自癌症受试者的血小板的蛋白质组发生了定量变化。目前尚不清楚 如果癌症引起的血小板蛋白变化仅作为生物标志物或促进疾病 进展。这一领域尚未解决的关键问题有可能为疾病提供新的见解 受血小板影响的机制。最近的研究表明蛋白质催化亚基的作用 血小板-癌症串扰中的磷酸酶 1 (PP1c)。我们的初步研究表明，血小板 从人类肺癌患者和患有实验性肺癌的小鼠中分离出的 PP1cα 有所增加 与非癌症对照相比的蛋白质。重要的是，血小板中 PP1cα 的条件性缺失表明 减少肺癌转移实验模型中的肿瘤负荷。我们的总体假设是 血小板 PP1cα 通过减少脱离诱导的细胞凋亡（失巢凋亡）和/或促进肺癌转移 促进免疫抑制环境。该提案将确定血小板 PP1cα 如何促进肺功能 使用新型小鼠模型和具有血小板磷酸酶、癌症专业知识的研究人员进行癌症转移 生物学、血小板癌串扰和肺癌免疫学。在目标 1 中，我们将研究 血小板 PP1cα 在肺癌存活和转移中的作用。目标 2 将确定血小板 PP1cα 对 对肺癌的免疫反应。这项工作可能会导致研究同时封锁 血小板/细胞外 PP1cα 以及免疫检查点可能提供独特的优化机会 癌症免疫疗法。