Employing biochemical and genetic approaches we are evaluating the requirement of tumour-specific metabolic pathways for different aspects of tumorigenesis.
Changes in the activity of metabolic pathways observed in tumours in comparison with normal tissues are associated either with the increased expression of specific enzymes or quite often with the expression of enzyme isoforms that are not expressed in normal tissue counterparts. For examples, our results demonstrated that increased glucose and glutamine catabolism in MYC-induced liver tumours is associated with the expression of regulatory enzyme isoforms distinct from the ones expressed in normal liver. MYC-induced liver tumours switch from glucokinase to hexokinase II (Hk2) to regulate the first step of glycolysis and from liver glutaminase (Gls2) to kidney glutaminase (Gls1) to regulate the first step of glutamine catabolism. Even though placed in a tissue-specific context, the pattern of metabolic enzyme isoforms found in MYC-induced liver tumours is also observed in MYC-induced lung tumours.
We use genetic and pharmacological approaches to manipulate the expression and activity of the enzymes regulating metabolic pathways in tumours. The goal is to evaluate the requirement of these specific enzyme isoforms and pathways of central carbon metabolism that they regulate, for various stages of tumourigenesis, including initiation, progression and metastasis. Using stable isotope-based metabolomics approaches in vivo we are evaluating the mechanisms underlying metabolic vulnerabilities and flexibilities of tumours induced by different genetic lesions in different tissues.