Mariia Yuneva: Projects

The role of glucose and glutamine metabolism in MYC-induced tumourigenesis

MYC proto-oncogene is involved in the genesis of multiple human cancers. MYC encodes a transcriptional factor that regulates the expression of multiple genes involved in cell proliferation, differentiation, growth and cell death. MYC is also a major regulator of cellular metabolism.

Our recent work demonstrated that MYC-induced liver tumours have increased catabolism of glucose into lactate and both increased glucose and increased glutamine catabolism through the Krebs cycle. 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 (Figure 2).

 

Figure 2

Figure 2. Metabolism of tumours can be determined by the initiating lesion and tissue of origin. MYC-induced liver tumours have increased glucose catabolism into lactate. They also have increased catabolism of both glucose and glutamine through the Krebs cycle. In contrast, MET-induced liver tumours do not have increased lactate production and have increased glutamine synthesis. Increased glucose and glutamine catabolism in MYC-induced liver tumours is associated with the expression of Hk2 hexokinase and Gls1 glutaminase isoforms. In MYC-induced lung tumours increased expression of Gls1 glutaminase is combined with increased expression of glutamine synthetase (GLUL), the enzyme responsible for the synthesis of glutamine from glutamate, suggesting that MYC-induced lung tumours can both consume and produce glutamine. (Click to view larger image)

Our experiments in vitro demonstrated that cells with increased expression of MYC are sensitive to glutamine deprivation (Figure 2) and inhibition of Gls1 expression and activity suggesting that Gls1 and glutamine metabolism can be plausible targets for the therapy of tumours with disregulated MYC activity.

We are employing transgenic mouse models as well as RNA interference (RNAi) technology to manipulate the expression of Hk2 and Gls1 in a tissue-specific manner. The goal is to evaluate the requirement of these specific enzyme isoforms and pathways of glucose and glutamine metabolism that they regulate, for various stages of MYC-induced tumourigenesis in different tissues. We are also interested in identifying novel metabolic pathways that may be required for MYC-induced tumourigenesis and can be exploited as potential therapeutic targets.

Figure 3

Figure 3. Cells with induced activity of MYC oncogene (MYCOn) die by apoptosis in the absence of glutamine. In the bottom panel cells that have nuclei with apoptotic morphology (fragmented or condensed) are indicated by arrows. (Click to view larger image)

Employing mouse models to evaluate the relationship between genetic lesions, tumour metabolism and tumour environment

Our results demonstrated that metabolism of tumours can be determined by the initiating lesion and by tissue of origin. Liver tumours induced by either MYC or MET oncogene have strikingly different changes in metabolism of glucose and glutamine, and metabolism of MYC-induced liver tumours varies from metabolism of MYC-induced lung tumours.

We are using stable isotope-based flux analysis with nuclear magnetic resonance (NMR) and mass spectrometry as well as genomic and biochemical analysis to evaluate metabolic changes and their requirement during tumourigenesis induced by different genetic lesions in various tissues. Most human cancers carry multiple genetic lesions. Each of those lesions may affect metabolism in a different way than the others. Therefore, we are also analysing metabolic changes and metabolic requirements of mouse tumours induced by combinations of genetic lesions found in human malignancies.

Evaluating the relationship between genetic lesions and metabolic changes in human cancers

The ultimate goal of our research is to come up with new metabolism-based strategies for the therapy of human cancers. We are developing in vivo systems where stable isotope-based metabolomics approach can be applied to comprehensively analyse metabolism of human tumours in the conditions close to their natural environment in a host organism.

We are interested in combining the obtained information about the metabolic changes with comprehensive genetic analysis to further understand lesion-metabolism relationship in a wide variety of human cancers.