Inflammation-induced niche remodelling in controlling melanoma dormancy

循环中的中性粒细胞是黑色素瘤患者预后不良的独立标志。我们认为，在炎症环境中，中性粒细胞的流入和中性粒细胞胞外陷阱(NET)的释放诱导了休眠黑色素瘤细胞的信号重编程。这是通过细胞外基质(ECM)成分在壁龛中由网络成分重塑，诱导黑色素瘤细胞上皮向间充质(EMT)转变，促进其扩散。此外，我们认为在非炎症环境中，DNA损伤剂的治疗会通过死亡的肿瘤或生态位内皮细胞诱导细胞外DNA的释放，激活不同于Net诱导的不同的信号通路，如cGAS/STING信号，从而导致肿瘤休眠的维持。我们将利用我们最近建立的体外黑色素瘤休眠模型，分析不同的细胞外基质成分以及利基内皮细胞和免疫细胞在诱导、维持或重新唤醒细胞周期停滞中的作用。我们将分析内皮细胞、免疫细胞和黑色素瘤细胞在壁龛中的串扰及其对休眠状态的影响。最后，我们将使用患者来源的播散性黑色素瘤细胞在合适的体内模型中验证我们的结果。

Circulating neutrophils are an independent marker of poor prognosis in melanoma patients. We propose that in an inflammatory environment neutrophil influx and neutrophil extracellular trap (NET) release induces a signal reprogramming in dormant melanoma cells. This is mediated by remodeling of extracellular matrix (ECM) components in the niche by NET components, which induces an epithelial to mesenchymal (EMT)-transition in the melanoma cells promoting their dissemination. Furthermore, we propose that in a non-inflammatory environment a therapy with DNA damaging agents induces a release of extracellular DNA by dying tumor or endothelial cells in the niche, that activates distinct signal pathways different from those induced by NETs such as cGAS/STING signaling, which results in maintenance of tumor dormancy. We will analyze the effect of different extracellular matrix components as well as endothelial and immune cells in the niche on induction, maintenance or reawakening of cell cycle arrest using our recently established in vitro melanoma dormancy model. We will analyze the crosstalk of endothelial cells, immune cells and melanoma cells in the niche and its effect on the dormant state. Finally, we will validate our results in suitable in vivo models using also patient-derived disseminated melanoma cells.