Principal Investigator
Our group investigates how the individual components of tissues work together to sustain organ function, homeostasis and repair. Herein we study the effect of metabolism on cellular programmes, and how this can affect disease progression.
Tissues adapt to insults such as wounding or infection with healing and regeneration. These processes are driven by changes in cellular states, such as de- and redifferentiation and the influx of specialized immune cells. Inevitably, the metabolic needs of these cells shift and are reflected in altered nutrient fluxes. It has now become clear that these fluxes can by hijacked during the development of diseases such as cancer or autoimmunity and are not mere bystander effects but instead are actively supporting the disease or might even be their root cause. We want to understand the relationship between metabolism and cellular as well as organismal health.
We believe that metabolism is more than the end product of a genetic programme and that consequently misdirected cellular metabolism can be the root cause of diseases rather than their mere manifestation.
Our group is interested in understanding metabolism at a cellular level. Individual cells within healthy or diseased tissues will have vastly different metabolic programmes. So far these have been very difficult to measure, due to a lack of analytical resolution. Using the novel technique of mass spectrometric imaging (MSI), we are tackling this problem, by directly measuring metabolism and metabolic fluxes in situ at a resolution that allows us to annotate the metabolism of individual cellular populations. We then use this knowledge to find ways to leverage metabolism with a curative intent.
Over the past years, we have developed several techniques in the field of MSI, which allowed us unprecedented insights into the metabolic architecture of tumours. This includes the tracing of metabolites into individual organelles, allowing us to identify cells with high metabolic demands. Furthermore we were able to stratify tumors by their metabolism and correlate these maps with expression of oncogenes. Using genetic models of breast cancer we were able to show that high levels of oncogenes make tumours dependent on Vitamin B5 to sustain a highly biosynthetic metabolism. This represents a unique metabolic vulnerability which can be exploited therapeutically.
Peter Kreuzaler, Matthew A. Clarke, Elizabeth J. Brown, Catherine H. Wilson, Roderik M. Kortlever, Nir Piterman, Trevor Littlewood, Gerard I. Evan and Jasmin Fisher, Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling. PNAS (2019)
Kreuzaler, P., Staniszewska, A., Li, W. et al. Stat3 controls lysosomal-mediated cell death in vivo. Nat Cell Biol13, 303–309 (2011). doi.org/10.1038/ncb2171
Principal Investigator