Dissection of TRAIL-mediated signaling in pancreatic ductal adenocarcinoma cells - towards efficient anti-tumor therapy

基于良好的肿瘤特异性活性，TRAIL目前被认为是一种很有前途的抗癌治疗候选生物反应调节剂。目前已经进行了几项TRAIL和激动型抗TRAIL受体抗体的临床研究，尽管已有临床前数据显示潜在的促肿瘤作用，但对TRAIL信号的详细剖析，特别是关于两种促凋亡TRAIL受体(TRAIL-RL和TRAIL-R2)各自的具体作用仍缺乏。此外，肿瘤间质对TRAIL-RL和TRAlL-R2信号的影响尚未得到解决。利用先进的技术分析细胞膜和细胞内受体复合体，以及共培养实验和动物模型，我们将进一步表征胰腺导管腺癌细胞(PDAC)中两种TRAIL受体的信号转导，并阐明其对肿瘤间质以及内源性TRAIL、肿瘤坏死因子和CD95L的依赖性。我们的项目将允许有选择地开发支持性治疗方式，最大限度地发挥TRAIL抗癌治疗的抗肿瘤作用，并抑制TRAIL抗癌治疗的增殖和转移副作用。

Based on a superior tumor-specific activity, TRAIL is currently viewed as a promising candidate biological response modifier for anti-cancer therapy. Several clinical studies with TRAIL and agonistic anti-TRAIL receptor antibodies are currently performed, although preclinical data showing potentially pro-tumoral effects have been reported and the detailed dissection of TRAIL-signaling especially regarding the specific roles of each of the two pro-apoptotic TRAIL- receptors (TRAIL-Rl and TRAIL-R2) is still missing. Furthermore, the influence of the tumor stroma on TRAIL-Rl and TRAlL-R2-signaling has not yet been addressed. Using sophisticated techniques to analyse membrane and intracellular receptor complexes as well as coculture experiments and animal models we will further characterize signaling of both TRAIL receptors in pancreatic ductal adenocarcinoma (PDAC) cells and clarify its dependance on tumor stroma as well as on endogenous TRAIL, TNF and CD95L. Our project will allow the development of supportive treatment modalities selectively maximizing the anti-tumor effect and suppressing proliferative and metastatic side-effects of TRAIL anti-cancer therapy.