Principal Investigator, MPI for Metabolism Research
PD Dr. Thomas Wunderlich and his working group explore the interaction between chronic inflammation and carcinogenesis. They focus on the progression of liver and colorectal cancers under obese conditions. PD Dr. Wunderlich’s scientific breakthroughs have included demonstrating the importance of interleukin 6 in liver cancerogenesis.
Our research: The human immune system combats not only invaders such as viruses and bacteria with an inflammatory response, but also tumors have been shown to be attacked by the immune system. Immunological tolerance develops when inflammation switches from acute to chronic conditions. Thus, the immune system can no longer attack tumor cells; they pro-liferate and can trigger cancer cell progression. The working group investigates the interaction between chronic inflammation associated with obesity and carcinogenesis in the liver and colon. Chronic inflammation plays a central role in these cancer entities as inflammatory mediators such as interleukin 6 promote the development of cancer in chronic inflammatory environments.
Our successes: In 2013 PD Dr. Wunderlich and his group enjoyed a scientific breakthrough when they decoded the importance of interleukin 6 in liver cancer development. In lean mice, IL-6 signaling is necessary to promote liver cancerogenesis via Mcl-1 stabilization, whereas in obese mice Mcl-1 stabilization occurs independnet of IL-6Rα signaling. Here, another yet to be identified factor that compensates in obesity for IL-6Rα deficiency activates similar signaling pathways that promote HCC development. Thus, identifying this factor might help to combat this often fatal disorder.
Our goals: In addition to promoting cancer, interleukin (IL) 6 and other inflammatory mediators also have beneficial metabolic characteristics for the human body. The research team aims to understand why IL 6 helps the body during acute inflammation, but has a negative effect under chronic inflammatory conditions.
Our methods/techniques: In addition to modern mouse genetics, PD Dr. Wunderlich and his group use metabolic as well as immunological methods including FACS analysis (fluorescence activated cell sorting).
Figure 1: Obesity promotes HCC development via Mcl-1 stabilization independent from IL-6Rα signaling. (A) Livers of 8-mo control and IL-6Rαxo mice injected with 25 mg/kg DEN at 15 days of age. (B) Quantitation of macroscopic tumor multiplicity determined by visual inspection in DEN-injected 8-mo control and IL-6Rαxo mice (n=15). (C) Cytochrome C release of isolated mitochondria after treatment with increasing concentrations of recombinant Bax. Mitochondria were isolated from naive 8-wk control and IL-6Rαxo mice fed a NCD. (D) Western blot analysis using cleaved caspase 3 and AKT antibodies on liver tissue from 8-wk control and IL-6Rαxo mice fed on a NCD sacrified at the indicated time points after a 100 mg/kg DEN injection. (E) Western blot analysis using Mcl-1, Bcl-2, Bcl-XL and Complex II antibodies on isolated mitochondria from DEN-injected 8-mo control and IL-6Rαxo mice.