Platelet Serine/Threonine Phosphatases in Cancer Pathophysiology

尽管筛查方法得到了改进，肺癌的五年存活率也取得了进展，但五年生存率仍为20% 治疗。肿瘤转移是导致癌症患者死亡的主要原因之一。除了不受监管的人 肿瘤细胞内信号转导与脱离诱导的肿瘤移位后的存活 (失巢)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 与最差的存活率和对化疗药物的低疗效有关。尽管血小板是一种 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)具有既定的作用 在心血管疾病方面，在癌症管理中部署时面临挑战。因此，新的 为了识别新的血小板靶点，需要更好地了解血小板-癌症串扰的方法。 有趣的是，癌症患者的血小板在蛋白质组中有数量上的变化。目前还不清楚 如果癌症引起的血小板蛋白变化(S)只是作为生物标志物(S)或促进疾病 进步。这一领域尚未解答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，蛋白质的催化亚单位有一个作用 磷酸酶1(PP1c)在血小板-癌症串扰中的作用。我们的初步研究显示，这些血小板 从人肺癌患者和实验性肺癌小鼠分离的PP1cα升高 蛋白质水平与非癌症对照组相比。重要的是，血小板中PP1cα的有条件删除显示 在肺癌转移的实验模型中降低肿瘤负担。我们最重要的假设是 血小板PP1cα通过减少脱落诱导的细胞凋亡和/或促进肺癌转移 促进免疫抑制的环境。这项提议将决定血小板PP1cα如何促进肺功能 利用新的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 肺癌的生物学、血小板-癌症串扰和免疫学。在目标1中，我们将调查 血小板PP1cα与肺癌生存和转移的关系AIM 2将确定血小板PP1cα在 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和免疫检查点可能提供独家优化机会 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.