Identifying feedback loop mechanisms between neutrophils and macrophages that cause sustained, pro-metastatic inflammation

识别中性粒细胞和巨噬细胞之间导致持续、促转移炎症的反馈循环机制

• 批准号: 422135538
• 负责人: Juliane Daßler-Plenker, Ph.D.
• 金额: --
• 依托单位: Cold Spring Harbor Laboratory
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422135538?language=en
• 关键词: Identifying; feedback; loop; mechanisms; between

Over half of breast cancer-related deaths are due to the recurrence of metastatic breast cancer five or more years after initial diagnosis and treatment [1]. Metastasis requires four key steps: 1) tumor cells leave the primary tumor; 2) tumor cells enter new tissue; 3) disseminated tumor cells (DTCs) re-initiate proliferation; and 4) an inflammatory, metastasis-supporting microenvironment is established. Steps 1-2 are rarely amenable to intervention, as they usually occur before the primary tumor is detected. However, targeting steps 3-4 may ultimately reduce metastasis and its associated mortality.To accomplish this long-term goal, we must first determine how the metastasis-supporting, inflammatory microenvironment is established. Inflammation is commonly mediated by neutrophils—essential cells of the innate immune system. In response to infection and inflammation, neutrophils release neutrophil extracellular traps (NETs)—meshes of genomic DNA with ~40 associated proteins—into the extracellular space to trap harmful microorganisms. However, NETs can also facilitate metastasis after a period of tumor dormancy. Dr. Mikala Egeblad’s lab recently discovered that sustained lung inflammation drives quiescent DTCs to re-initiate proliferation in mice (step 3) and that NETs are essential to this process. My new preliminary data show that NET-associated proteins, e.g. high mobility group box 1 (HMGB1), can activate macrophages to secrete inflammasome-dependent interleukin (IL)-1ß, which in turn induces more NETs. I therefore hypothesize that a NET-macrophage feedback loop drives step 4 of the metastatic process. In aim 1, I will identify how macrophages sense NETs to induce IL-1ß secretion in vitro and in vivo, setting the stage for future experiments targeting this pathway. In aim 2, I will test the effects of NET-induced IL-1ß on the establishment of metastasis from quiescent DTCs. Three different IL-1ß blocking therapies are already approved for rheumatoid arthritis, so if NET-induced IL-1ß promotes metastasis from quiescent DTCs in the proposed models, these drugs could be tested in cancer therapy.

超过一半的乳腺癌相关死亡是由于转移性乳腺癌在初次诊断和治疗五年或更长时间后复发所致[1]。转移需要四个关键步骤：1）肿瘤细胞离开原发肿瘤； 2）肿瘤细胞进入新组织； 3）播散性肿瘤细胞（DTC）重新开始增殖； 4) 建立炎症、支持转移的微环境。步骤 1-2 很少需要干预，因为它们通常发生在检测到原发肿瘤之前。然而，针对步骤 3-4 可能最终会降低转移及其相关死亡率。为了实现这一长期目标，我们必须首先确定如何建立支持转移的炎症微环境。炎症通常由中性粒细胞（先天免疫系统的必需细胞）介导。为了应对感染和炎症，中性粒细胞将中性粒细胞胞外陷阱 (NET)（由基因组 DNA 与约 40 种相关蛋白组成的网状结构）释放到细胞外空间以捕获有害微生物。然而，NETs 也可以在肿瘤休眠一段时间后促进转移。 Mikala Egeblad 博士的实验室最近发现，持续的肺部炎症会驱动静止的 DTC 在小鼠体内重新启动增殖（第 3 步），而 NET 对此过程至关重要。我的新初步数据表明 NET 相关蛋白质，例如高迁移率族蛋白 1 (HMGB1) 可以激活巨噬细胞分泌炎症小体依赖性白细胞介素 (IL)-1ß，进而诱导更多 NET。因此，我假设 NET 巨噬细胞反馈回路驱动转移过程的第 4 步。在目标 1 中，我将确定巨噬细胞如何感知 NET 以在体外和体内诱导 IL-1ß 分泌，为未来针对该途径的实验奠定基础。在目标 2 中，我将测试 NET 诱导的 IL-1ß 对静止 DTC 转移建立的影响。三种不同的 IL-1ß 阻断疗法已被批准用于治疗类风湿性关节炎，因此，如果 NET 诱导的 IL-1ß 在所提出的模型中促进静止 DTC 的转移，那么这些药物可以在癌症治疗中进行测试。