Interconnected ganglia

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Oncogenes and tumour metabolism

Project supervisor: Mariia Yuneva (Developmental Neurobiology)

Changes in metabolism of two major nutrients, glucose and glutamine, are observed in various cancer types. These changes are often associated with the expression of tumour-specific enzyme isoforms that are not expressed in parental tissues. Although altered metabolism is thought to provide transformed cells with the advantage in proliferation and survival, transformation can also make cells addicted to metabolic changes (Yuneva et al, 2007). Thus, inhibition of tumour-specific enzyme isoforms and metabolic pathways may prove to be effective for the elimination of transformed cells without affecting normal tissues.

Various oncogenes involved in the genesis of human cancers are known to regulate the expression and activity of different metabolic enzymes and can differently affect the metabolic-dependence of transformed cells (Yuneva et al, 2007; Yuneva et al, 2012). However, the relationship between specific oncogenes and metabolic changes in the context of a whole organism and complex tumour microenvironment of specific tissues has not been evaluated. Our recent results demonstrated that glucose and glutamine metabolism of tumours can indeed be defined by both an initiating lesion and tissue of origin (Yuneva et al, 2012).

The aim of this project is to evaluate the requirement of tumour-specific enzyme isoforms and the pathways regulated by these enzymes for the initiation and progression of tumours induced by a defined oncogenic event in different mouse tissues, including liver, lung and mammary gland. Mouse genetics as well as molecular biological approaches will be used to manipulate the expression of tumour-specific enzyme isoforms in a tissue-specific manner. The effect of these manipulations on tumour metabolism will be assessed by nuclear magnetic resonance (NMR) and mass spectrometry.

Finally, the molecular mechanisms of tumour dependence/independence on identified metabolic pathways will be addressed. The project will provide training in genetic, biochemical and molecular biology techniques as well as training in cell biology and bioinformatics.

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