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

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后5年或更长时间的复发[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）重新启动增殖;以及4）建立炎性的、支持转移的微环境。步骤1-2很少适合干预，因为它们通常发生在检测到原发性肿瘤之前。然而，靶向步骤3-4可能最终降低转移及其相关死亡率。为了实现这一长期目标，我们必须首先确定支持转移的炎症微环境是如何建立的。炎症通常由先天免疫系统的嗜中性粒细胞-必需细胞介导。在感染和炎症反应中，中性粒细胞释放中性粒细胞胞外陷阱（NETs）-基因组DNA与约40种相关蛋白质的网格-进入细胞外空间以捕获有害微生物。然而，NET也可以促进肿瘤休眠一段时间后的转移。Mikala Egeblad博士的实验室最近发现，持续的肺部炎症驱动静止的DTC重新启动小鼠的增殖（步骤3），而NET对这一过程至关重要。我的新的初步数据表明，NET相关蛋白，例如高迁移率族蛋白1（HMGB 1），可以激活巨噬细胞分泌炎性小体依赖性白细胞介素（IL）-1 β，从而诱导更多的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在体外和体内感应NET诱导IL-1 β分泌，为未来针对此途径的实验奠定基础。在目标2中，我将测试NET诱导的IL-1 β对从静止DTC建立转移的影响。三种不同的IL-1 β阻断疗法已经被批准用于类风湿性关节炎，因此，如果NET诱导的IL-1 β在拟议的模型中促进静止DTC的转移，这些药物可以在癌症治疗中进行测试。

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.