Inflammation-induced niche remodelling in controlling melanoma dormancy

炎症诱导的生态位重塑控制黑色素瘤休眠

• 批准号: 456263798
• 负责人: Professorin Dr. Birgit Schittek
• 金额: --
• 依托单位: Sektion Dermatologische Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/456263798?language=en
• 关键词: Inflammation; induced; niche; remodelling; controlling

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.

循环中性粒细胞是黑色素瘤患者预后不良的独立标志物。我们提出，在炎症环境中，中性粒细胞流入和中性粒细胞胞外陷阱（NET）的释放诱导休眠的黑色素瘤细胞的信号重编程。这是通过NET组分重塑壁龛中的细胞外基质（ECM）组分介导的，NET组分诱导黑色素瘤细胞中的上皮向间充质（EMT）转化，促进其传播。此外，我们提出，在非炎症环境中，使用DNA损伤剂的治疗通过使肿瘤或微环境中的内皮细胞死亡来诱导细胞外DNA的释放，这激活了与NET诱导的那些不同的信号途径，例如cGAS/STING信号传导，这导致肿瘤休眠的维持。我们将使用我们最近建立的体外黑色素瘤休眠模型分析不同细胞外基质成分以及小生境中的内皮细胞和免疫细胞对细胞周期阻滞的诱导、维持或重新唤醒的影响。我们将分析内皮细胞、免疫细胞和黑色素瘤细胞在小生境中的串扰及其对休眠状态的影响。最后，我们将验证我们的结果在合适的体内模型，也使用患者来源的播散性黑色素瘤细胞。