Platelet Serine/Threonine Phosphatases in Cancer Pathophysiology

肺癌的五年生存率约为20%，尽管筛查方法有所改进， 治疗肿瘤转移是癌症患者死亡的主要原因之一。除了失调 肿瘤细胞中的信号传导，从肿瘤诱导的凋亡中移出的循环肿瘤的存活 血液中的失巢凋亡（anoikis）和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 与最差的存活率和对化疗剂的较低功效相关。虽然血小板是一种 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，当用于癌症管理时具有挑战性。因此，新 需要更好地理解血小板-癌症串扰的方法来鉴定新的血小板靶。 有趣的是，来自癌症受试者的血小板在蛋白质组中具有定量变化。目前未知 如果癌症诱导的血小板蛋白的变化仅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 血小板影响的机制。最近的研究表明，蛋白质的催化亚基 磷酸酶1（PP 1c）在血小板癌串扰。我们的初步研究显示血小板 从人肺癌患者和实验性肺癌小鼠中分离的PP 1c α 蛋白质与非癌症对照相比。重要的是，血小板中PP 1c α的条件性缺失显示， 在肺癌转移的实验模型中降低肿瘤负荷。我们的首要假设是 血小板PP 1c α通过减少脱落诱导的细胞凋亡（失巢凋亡）促进肺癌转移和/或 促进免疫抑制环境。这项提案将确定血小板PP 1c α如何促进肺 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-癌症串扰和肺癌免疫学。在目标1中，我们将研究 血小板PP 1c α在肺癌生存和转移中的作用目的2：探讨血小板PP 1c α在血小板活化中的作用。 对肺癌的免疫反应。这项工作可能会导致研究，其中同时封锁 血小板/细胞外PP 1c α沿着免疫检查点可能提供了优化 癌症免疫疗法

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.