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最初诊断和治疗5年或更长时间后复发所致。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；4)建立炎症性、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原发肿瘤被发现之前。然而，靶向步骤3-4可能最终减少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。炎症通常是由中性粒细胞介导的，中性粒细胞是先天免疫系统的基本细胞。在对感染和炎症的反应中，中性粒细胞释放中性粒细胞胞外陷阱(NETs) -基因组DNA与约40种相关蛋白的网状物-进入细胞外空间以捕获有害微生物。然而，NETs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，持续的肺部炎症会促使静止的dtc在小鼠体内重新启动增殖（步骤3），而NETs对这一过程至关重要。我的新初步数据表明，net相关蛋白，如高迁移率组框1 (HMGB1)，可以激活巨噬细胞分泌炎性小体依赖性白细胞介素(IL)-1ß，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。在目的1中，我将确定巨噬细胞如何感知net诱导IL-1ß分泌，在体外和体内，为未来针对这一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阻断疗法已经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。

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.