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。最近，坏死性凋亡被确定为一种新的形式的程序性坏死。然而，其在大肠癌中的功能尚未报道。在持续资助期间进行的研究表明，坏死性凋亡调节因子RIP 3和caspase-8在肠上皮细胞的稳态中具有重要功能，并表明该途径在肠肿瘤发生中的作用。事实上，我们已经在初步研究中表明RIP 3具有促肿瘤作用。在本提案中，我们将利用已建立的散发性和炎症诱导和转移性结肠癌的小鼠模型来研究坏死性凋亡的功能作用。特别是，我们将阐明和巩固的坏死性凋亡调节RIP 3和caspase-8的启动，促进和发展的结直肠癌。该提案的另一个目的是确定发育异常上皮细胞中RIP 3依赖的信号通路。基于初步数据，RIP 3对WNT途径的影响将被深入研究。此外，将比较来自RIP 3熟练和缺陷小鼠的肿瘤样品的转录组和蛋白质组差异。最后，我们将研究坏死性凋亡的调节是否对治疗结直肠癌的既定化疗药物（如5-FU）和创新治疗方法（如SMAC模拟物）的治疗（肿瘤细胞杀伤）效果产生影响。总之，该提案旨在描述坏死性凋亡在结直肠癌中的作用，并将测试坏死性凋亡调节因子的调节是否对肿瘤发展有影响。这项研究将有助于更广泛地了解结直肠癌中的细胞死亡调节，并可能有助于新的创新治疗方法。

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.