We are interested in the interplay of cancerous tissue and the tumor host organism. A prominent example of the deleterious effects of tumor growth for its host organism is described by the term cancer associated cachexia(CAC). Essentially, it is thought that tumors release soluble factors including IL-6, other cytokines and chemokines that cause this wasting syndrome. CAC is often the direct cause of cancer deaths. We have found that the rate limiting enzyme of cellular triglyceride catabolism, adipose triglyceride lipase (ATGL) plays an important role in CAC induction in murine cancer models. Follow the link to the article: http://science.sciencemag.org/content/333/6039/233.long
Further Research focused on the role of the tumor hosts lipoprotein metabolism and its influence on tumor cell metabolism and tumor growth. Essentially we found that certain tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Treatment with the lipid lowering drug fenofibrate however, reversed this effect. Follow the link to the article: https://www.sciencedirect.com/science/article/pii/S1388198113000978?via%3Dihub
To assess whether tumor progression was truly dependent on tumor-induced hyperlipidemia, we utilized a VLDL production-deficient mouse model. Strikingly, tumor weight was reduced in in these mice due to their modified lipoprotein metabolism in the liver, resulting in reduced LDL cholesterol support for tumor growth. Follow the link to the article: https://www.sciencedirect.com/science/article/pii/S2211124716302613?via%3Dihub
On the same topic we are currently focusing on the role of ATGL derived fatty acids as regulators of the cellular lipogenesis.
To further understand how to exploit metabolic needs of cancer cells as therapeutic targets for the treatment of cancer we have also implemented a mouse embryonic fibroblast (MEF) model to study the metabolic adaptions of normal cells when they spontaneously progress to an immortalized state . We observed that upon immortalization, cells adapt to become bioenergetically more efficient by increasing respiratory reserve capacity to survive metabolic stress. In addition, they exhibit a higher degree of dependency to glutamine compared to normal cells, suggesting an increased flux of glutamine derived intermediates for biomass production (Figure).
Future Metabolic labelling experiments should help us to determine the fate of important metabolites in early, old and immortalized MEFs.