Bidirectional interaction of platelets and tumor cells in patients with glioblastoma

项目总结 胶质母细胞瘤是所有癌症中致死率最高的癌症之一，也是最常见的原发恶性脑瘤， 通常会在15个月前致命。在最初的肿瘤切除后，我们依赖于一种不完美的疾病反应衡量标准， 即磁共振脑成像，因为在复发时获取肿瘤组织通常是危险的或不能 影响存活率，很少进行手术。事实上，许多患者仅依靠微小的活组织检查就能初步诊断为 没有能力进行后续的深层分子分析，更不用说随着时间的推移监测疾病了。海流 提议将解决基础设施管理领域的一个根本差距，即缺乏不依赖于 肿瘤组织的可用性以及那些能够提供实时的、无组织的肿瘤监测，这尤其是 在监测治疗反应和纵向评估疾病进展方面至关重要。以血为本 循环中的肿瘤细胞和游离DNA等生物标记物很有吸引力，但尚未提供有意义的 结果是基底膜(与其他癌症相比)，尚未成为临床诊断。肿瘤教育 最近有报道称，血小板(TEP)含有肿瘤特异性基因表达信号 它们与几种肿瘤类型的预后相关，但其临床价值和机制 TEP的浓缩性尚不清楚。这项建议的总体目标是阐明潜在的机制 肿瘤细胞与血小板的相互作用导致TEP并开发一种基于TEP的液体活检平台 GBM患者疾病的纵向监测。在这个项目中，我们将检验这一假设 骨髓中的肿瘤信号和血小板吸收肿瘤的信号会导致数量增加- 以PDPN依赖的方式获得含有RNA货物的细胞外小泡。TEP RNA签名反映了 潜在的肿瘤生物学、生长和治疗耐药性，并将被用作生物标记物。 在目标1中，我们将检验促炎症细胞因子介导的副肿瘤的假设 血小板增多症促进GBM中TEP信号的形成。在目标2中，我们将检验PDPN假设 与CLEC2受体的相互作用有助于将RNA从肿瘤细胞转移到血小板。在《目标3》中，我们将 验证TEP RNA签名可用于纵向监测患者疾病负担的假设 使用GBM。

PROJECT SUMMARY Glioblastoma is among the most lethal of all cancers and the most common primary malignant brain tumor, typically lethal by 15 months. After initial tumor resection, we rely on an imperfect measure of disease response, namely magnetic resonance brain imaging, as obtaining tumor tissue at recurrence is often dangerous or fails to impact survival and is rarely performed. Indeed, many patients rely only on a tiny biopsy for initial diagnosis with no ability for subsequent deep molecular analyses, let alone monitoring of disease over time. The current proposal will address a fundamental gap in the field of GBM, i.e. the lack of predictors not dependent on the availability of tumor tissue and those that can provide real-time, tissue-free tumor monitoring, which is particularly critical in monitoring treatment response and assessing disease progression longitudinally. Blood-based biomarkers such as circulating tumor cells and cell free DNA are attractive, but have yet to provide meaningful results in GBM (compared to other cancers) and have yet to become clinical diagnostics. Tumor educated platelets (TEPs) has recently been reported and shown to contain tumor-specific gene expression signatures that are associated with outcome for several tumor types, but the clinical value and the mechanisms of enrichment of TEPs are unknown. The overall goals of this proposal are to elucidate the mechanism underlying the tumor cell–platelet interaction that leads to TEPs and to develop a TEP-based liquid biopsy platform for longitudinal monitoring of disease in patients with GBM. In this project, we will test the hypothesis that platelet numbers are increased in response to tumor signaling in the bone marrow and that platelets take up tumor- derived extracellular vesicles containing RNA cargo in a PDPN dependent manner. TEP RNA signatures reflect underlying tumor biology, growth, and treatment resistance, and will be utilized as biomarkers. In Aim 1, we will test the hypothesis that pro-inflammatory cytokine-mediated paraneoplastic thrombocytosis promotes formation of TEP signatures in GBM. In Aim 2, we will test the hypothesis that PDPN interaction with the CLEC2 receptor contributes to transfer of RNA from tumor cells to platelets. In Aim 3, we will test the hypothesis that TEP RNA signatures can be used to monitor disease burden longitudinally in patients with GBM.