Investigation of caspase-8 regulation and function in the development of colorectal cancer

结直肠癌是西方世界最常见的癌症。肠上皮细胞在结肠癌的发生发展中起着至关重要的作用。对细胞死亡的抵抗是肿瘤发展的主要驱动力。近年来，坏死性上睑下垂被认为是一种新型的程序性坏死。然而，其在结直肠癌中的作用尚未见报道。在正在进行的资助期间进行的研究表明，坏死下垂调节因子RIP3和caspase-8在肠上皮的动态平衡中具有重要作用，并表明这一途径在肠道肿瘤发生中发挥了作用。事实上，我们在初步研究中已经表明，RIP3具有促进肿瘤的作用。在目前的方案中，我们将利用已建立的散发性和炎症诱导的和转移性结肠癌的小鼠模型来研究坏死性下垂的功能作用。特别是，我们将阐明和巩固坏死下垂调节因子RIP3和caspase-8在结直肠癌的启动、促进和进展中的作用。该提案的另一个目标是确定发育不良的上皮细胞中依赖RIP3的信号通路。在初步数据的基础上，将深入研究RIP3对WNT途径的影响。此外，还将比较RIP3熟练小鼠和RIP3缺陷小鼠的肿瘤样本在转录和蛋白质组学方面的差异。最后，我们将研究坏死下垂的调节是否会影响现有化疗药物(如5-FU)和创新治疗方法(如Smac类似物)在结直肠癌治疗中的治疗(肿瘤细胞杀伤)效果。综上所述，该提案旨在表征坏死性下垂在结直肠癌中的作用，并将测试坏死性下垂调节剂的调节是否对肿瘤的发展有影响。这项研究将有助于更广泛地了解结直肠癌细胞死亡的调控，并可能为新的创新治疗方法做出贡献。

Colorectal cancer is the most common cancer in the Western world. Intestinal epithelial cells play a crucial role in the development of colon cancer. Resistance to cell death is a a major driver of tumor development. Recently necroptosis was identified as a novel form of programmed necrosis. However its function in colorectal cancer has not yet been reported. Studies performed during the ongoing funding period demonstrate important functions of the necroptosis regulators RIP3 and caspase-8 in the homeostasis of the intestinal epithelium and suggest a role of this pathway in intestinal tumorigenesis. In fact, we have shown in preliminary studies that RIP3 has a tumor-promoting effect. In the present proposal we will take advantage of established mouse models for sporadic and inflammation-induced and metastatic colon cancer to study the functional role of necroptosis. In particular, we will elucidate and consolidated the necroptosis regulators RIP3 and caspase-8 in initiation, promotion and progression of colorectal cancer. Another objective of the proposal is to identify RIP3-dependent signaling pathways in dysplastic epithelial cells. Based on preliminary data, the influence of RIP3 on the WNT pathway will be intensively studied. In addition, tumor samples will be compared from RIP3 proficient and deficient mice for transcriptomic and proteomic differences. Finally, we will investigate whether modulation of necroptosis has an effect on the therapeutic (tumor cell killing) effect of established chemotherapeutic agents in the treatment of colorectal cancer such as 5-FU and innovative therapeutic approaches, such as SMAC mimetics. In summary, the proposal aims to characterize the role of necroptosis in colorectal cancer and will test whether modulation of necroptosis regulators has an effect on tumor development. The study will contribute to a broader understanding of cell death regulation in colorectal cancer and possibly to new innovative therapeutic approaches.