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

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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.