Projects

Decoding Metabolic regulation


Understanding the regulation of metabolism in vitro (cell cultures) but also in vivo is at the core of our interest. Using the established mass spectrometry based metabolomics and proteomics methods we investigate metabolic dys-regulation in cancer and muscular dystrophies. Recently we build up a metabolomics platform for the Berlin Institute of Health aiming to develop metabolomics towards a tool for systems medicine and personalized medicine.

 

Illustration of the analytical strategies (I) investigating the cellular metabolism as a defined metabolic network and (II) analyzing the metabolic composition of blood that reflects the metabolic interplay of the different organs and the metabolic state in health and disease.


Metabolic reprogramming


Metabolic reprogramming occurs during differentiation of stem cells, immune cell activation and also during oncogenic transformation. In the next years we envision to use the established proteomics and metabolomics tools to decode the molecular basis and function of such reprogramming events. During stem cell differentiation a shift of the cellular metabolism occurs. These events include the activation of mitochondrial metabolism detectable by increasing flux through TCA cycle intermediates. Interestingly, the state of the mitochondrial metabolism is very different between stem cells and cancer despite the fact that both cell types depend on glycolytic metabolism and show high rates of lactic acid production in cell culture (Warburg effect).


Metabolic alterations during stem cell differentiation

By comparing the glycolytic activity of stem cells and cancer cells similar glucose derived fluxes can be measured. However, the steady state levels of glycolytic intermediates are quite different. Also the proteomic profiles between various cancer cell lines and stem cell differ at the isoenzyme level. We conclude that even though the Warburg effect can be observed in both conditions the underlying molecular machinery may be distinct. We aim to analyze the metabolic machines of stem cells and cancer cells and to correlate the results with metabolomics data to understand the difference between stem cell and cancer cell metabolism. Ultimately, we aim to understand if cancer cell metabolism can be targeted without disturbing proliferating cells in a healthy organism.

Analysis of cancer cell metabolism

Cancer cells display a high metabolic activity allowing them to grow in a competitive manner inside the body. Those cells take advantage over neighboring cells by metabolizing faster the available resources, mainly glucose, glutamine and oxygen. An up-regulation of glycolysis and the resulting lactate formation of many tumors was already observed and described nearly 90 years ago by the Nobel laureate Otto Heinrich Warburg. Warburg termed this effect ‘aerobic glycolysis’ because he observed lactate formation, a product of an anaerobic metabolism, by tumor cells even in the presence of oxygen. The increased metabolic rates of cancer cells induce very fast a gradient of nutrient availability and produce an environment where glucose and oxygen become limiting. It is expectable that the cellular signaling and metabolic networks adjust to these conditions. Furthermore, we propose that cells respond differently to therapy upon altered environmental conditions even if the underlying genome is the same. We have started to characterize cancer cell metabolism in regard to nutrient availability. We often observed that metabolic activities are not necessarily reflected in the abundance of proteins or even in the steady-state levels of metabolites. Beyond being regulated simply by the expression levels of enzymes, the cellular metabolic pattern is influenced also by the isoform composition of the enzymatic network and its regulatory properties. Our lab participates in the e:Bio projects 'Hepatomasys' and 'Oncopath' aiming to decode the molecular interaction between the cellular signaling network and metabolism.

 

Model of the metabolic heterogeneity of solid tumors. The scheme illustrates the different zones of solid tumors classified by nutrient availability

 

We speculate that further metabolic pathways support proliferation of cancer cells. We and others found that nearly no glucose-derived carbon entered mitochondria and that glutamine was the carbon source for the tricarboxylic acid cycle (TCA-cycle). Further, we have evidence that this metabolic activity depends on oxygen levels. However, till now there is no clear evidence that cancer cells display such high glutamine consumption in vivo

 

Distribution of carbon atoms derived from glucose or glutamine within the central carbohydrate metabolism of cancer cells. Cancer cells were incubated with stable isotope labeled glucose and glutamine and the resulting distribution of carbon atoms was analyzed using stable isotope resolved metabolomics (SIRM)