The role of Mcl-1 for intestinal mucosa homeostasis and the colorectal carcinoma

• Applicant: Privatdozent Dr. Bruno Christian Köhler
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 363832424

The proposed project focusses on the role of the antiapoptotic protein Mcl-1 for the intestinal mucosa and colorectal carcinogenesis. We were able to show that antiapoptotic Bcl-2 proteins, such as Bcl-2 itself, Bcl-xL and Mcl-1, exert functions in colorectal cancer cells, reaching beyond known cell death regulatory properties. Antiapoptotic Bcl-2 proteins regulate migration and invasiveness of colorectal cancer cells, thereby contributing to the aggressiveness of the disease. Furthermore, we were able to show that autophagy is blocked in presence of a pan-Bcl-2 inhibitor. Since the process of autophagy can protract cell death induction under unfavorable conditions, this finding is also very important in the context of intestinal tumorigenesis. To further dissect protein functions in vivo, intestine-specific knockout mice for Mcl-1 and Bcl-xL have already been established in our group. We have recently demonstrated that an intestine specific knockout of Bcl-xL diminished the susceptibility towards chemically induced carcinogenesis by inducing apoptosis.Our previous work emphasizes a unique role of Mcl-1 for the intestinal mucosa. In patients facing a higher risk of developing colorectal carcinomas due to chronic alcohol consumption, Mcl-1 was found to be significantly upregulated. Moreover, intestine specific deletion of Mcl-1 in mice causes a strong phenotype. Mice lacking Mcl-1 in intestinal epithelial cells exhibit severe mucosal damage, inflammation and ultimately development of carcinomas. The proposed project aims at the mechanistic elucidation of the mentioned phenotype and in-depth functional analyses of Mcl-1 in the mucosa. Therefore, crossbreeding of mice with intestine specifically deleted Caspase 8 mice and RIP3 deficient mice are planned. Crossbreedings aim at dissecting the contribution of necroptosis and apoptosis for the phenotype of intestine specific Mcl-1 knockout mice. In a second part of the project, the application of small molecule inhibitors of Mcl-1 in vitro, ex vivo and in a murine model of chemical carcinogenesis are planned. Targeting Mcl-1 on various points within the process of sequential colorectal carcinogenesis may further uncover its contribution for onset, progression and metastasation of colorectal carcinomas. The third part of the project utilizes organotypic cultures (Organoids, Mini-guts) to study the functional role of Mcl-1 for organogenesis of the intestine and differentiation of intestinal epithelial cells.In summary, this projects aims at uncovering the role of Mcl-1 for intestinal mucosa homeostasis as well as for initiation and progression of colorectal carcinomas. Our preliminary work provides a strong scientific background for the proposed experiments. In vitro, ex vivo and in vivo studies may comprehensively analyze Mcl-1 function from intestinal organogenesis to malignant transformation of the intestinal epithelium.

• DFG Programme: Research Grants