Using mouse models to understand the impact of rewired metabolism and inflammatory processes on cancer development and progression
Obesity is a steadily increasing health burden that affects more than 600 million people worldwide. While classical obesity-associated disorders, such as the development of type 2 diabetes and fatty liver disease, have been major research foci over recent years, research on the predisposition to develop certain cancer entities under obese conditions is still in its infancy. In particular, cancer types that depend on an inflammatory tumour microenvironment (TME), such as hepatocellular and colorectal carcinoma, are mainly affected by obesity. Thus, one of the key questions we are addressing is how obesity predisposes the body to cancer. This process might involve not only excess nutrients and the development of insulin resistance, but also chronic low-grade inflammation that is caused by activated immune cells in white adipose tissue (WAT) and liver. These immune cells comprising macrophages, T cells, NK cells, as well as B cells are activated via adipose stress. In turn, inflammatory cytokines, such as IL-6 and TNF, are released into the circulation and are causative for the low grade inflammatory state in obesity. Interestingly, IL-6 and TNF are also present in the TME of most cancer entities. Thus, we hypothesize that the chronic low grade inflammation present under obese conditions promotes hepatocellular carcinoma (HCC) and colorectal cancer (CRC). Of note is that while the roles of IL-6 and TNF have been studied intensively in cancer models, the cell-type-specific contribution of these inflammatory mediators and their underlying molecular mechanisms still remain elusive. To better understand these processes, our group uses sophisticated genetic mouse models in combination with dietary intervention and chemical-induced cancerogenesis. The main focus of the group lies on deciphering both the cellular and molecular mechanisms of obesity-associated HCC and CRC development. To achieve this goal, we established diet-induced obesity in the dietylnitrosamine (DEN)-induced mouse model of liver cancer as well as the azoxymethane/dextransufate (AOM/DSS) model of colon cancerogenesis. Importantly, we can recapitulate the clinical findings that obesity affects cancer development and progression in our models, thereby allowing us to investigate the underlying molecular and cellular mechanisms as a first step in obtaining new and profound insights into these diseases.