Our goal is to understand how metabolism of tumours is shaped by their genetic composition, environmental factors and the interactions between cells composing a tumour.
One of the main challenges in designing efficient and specific anti-cancer therapies is tumour heterogeneity. Cell metabolism is regulated during normal cell development and proliferation by the same factors that, when dysregulated, are involved in the initiation of tumorigenesis. Our results demonstrated that different tumour-initiating lesions can result in tumours with different metabolism. Furthermore, the metabolism of tumours is determined by the tissue a tumour originates from. For example, liver tumours induced by either MYC or MET oncogene have strikingly different changes in metabolism of glucose and glutamine (Figure 2), and metabolism of MYC-induced liver tumours varies from metabolism of MYC-induced lung tumours.
Each tumour can contain cells carrying different genetic lesions resulting in inter and intra-tumour metabolic heterogeneity. Furthermore, tumour cells interact with other cell types composing a tumour, including blood vessel cells, immune cells and tumour associated fibroblasts. All of these cells influence each others metabolism determining metabolic requirements and vulnerabilities of tumour cells and contributing to the metabolic heterogeneity. Last but not least, metabolism of cells in different tumour regions is influenced by differential supply of oxygen and nutrients throughout a tumour.
Using stable isotopes (molecules carrying additional atoms of either carbon, nitrogen or hydrogen) and metabolomics analytical platforms, such as nuclear magnetic resonance, gas chromatography and liquid chromatography mass spectrometry, we are evaluating how metabolism is changed in tumours induced by different genetic lesions in different tissues. To be able to dissect the inter-tumour heterogeneity and metabolic interactions between different cellular components of a tumour we are employing mass spectrometry imaging modalities, MALDI, DESI and SIMS, which is done in collaboration with National Physical Laboratory.