Cardio-Oncology * Metabolism
We propose that the metabolic phenotype of cancer cells promotes metabolic and structural remodeling in the cardiac and skeletal muscle cells. This is important because, understanding how metabolic alterations initiate and sustain structural remodeling will allow us to identify liabilities and open therapeutic avenues. Ultimately this knowledge will enable us to identify patient populations susceptible to therapies and manage risk stratification of CVDs in cancer patients.
Mutations of metabolic enzymes are genetically defined metabolic alterations. In cancer cells these changes contribute mechanistically to tumor progression and transformation. This paradigm is best described for mutations of the isocitrate dehydrogenase (IDH), which is present in a subset of solid tumors and leukemias. IDH converts isocitrate to alpha-ketoglutarate in a decarboxylation and reduction reaction. IDH mutations are gain of function mutations and lead to the production of an oncometabolite called D2-hydroxyglutarate (D2-HG). Our work shows that accumulation and release of D2-HG by cancer cells promotes cardiac metabolic and proteomics remodeling. D2-HG impairs cardiac oxidative metabolism by inhibiting alpha-ketoglutarate dehydrogenase in the Krebs cycle.
We use mathematical modeling to identify which pathways are affected in the heart at a systems level during disease development. We integrate experimental data into a mathematical genome-scale model of cardiac metabolism, called CardioNet. The model comprises over 900 metabolites and almost 2000 metabolic reactions that are assigned to six compartments. CardioNet can be used to visualize and analyze various data from metabolite level to proteome information to gene expression data and allows to conduct mathematical modeling on a genome-scale.