Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

Periodic Report Summary 1 - METABOLISMCONNECT (Can metabolic states induced by diabetes and obesity promote cancer?)

It has emerged in recent years that many of the signaling factors commonly altered in cancer cells target metabolic genes. An altered metabolism allows cancer cells to sustain their proliferative needs. Yet, whether altered metabolic fluxes and metabolite concentrations, which define the metabolic state of a cell, are only a consequence or can be a cause of cancer is unknown. The latter is supported by epidemiological studies showing that patients suffering from diabetes or obesity have an increased risk to develop cancer.
We elucidate whether metabolic states can initiate liver cancer, which is in 30% of the cases associated with diabetes and obesity. Our final goal is to unravel the causal link between the increased liver cancer risk and the metabolic syndrome. We measure metabolite concentrations and metabolic fluxes in tumorigenic versus non-tumorigenic liver cells in vitro, and in a diet and carcinogen induced mouse model in vivo. Integrating the in vivo and in vitro data will allow us to identify which metabolic states induced by diet promote liver cancer. Elucidating the metabolic interface between cancer onset and diet will provide a mechanistic understanding of tumor initiating events in patients suffering from the metabolic syndrome and ultimately lead to new therapeutic strategies to prevent increased tumor events in such patients.

In the first two years of this project we have metabolically characterized tumorigenic liver cancer cell lines and non-malignant hepatocyte cell lines. Moreover, we have established in the laboratory in vivo 13C tracer analysis, which will not only allow us to determine metabolite concentrations of liver tumors in mice but also metabolic active pathways and reactions. This extend to the original project allows us to specifically map differentially active reactions between in vivo and in vitro metabolic states and will promote the translation of our research findings. Finally, we selected a suitable diet induced liver cancer model and generated time dependent samples of normal liver and liver cancer for metabolomics and 13C tracer analysis. We found that liver cancer cell lines show specific alterations in central metabolism that are not present in non-malignant hepatocyte cell lines. Moreover, high fat diet promoted significantly liver cancer. Thereby, we can trace with high resolution metabolic states in central metabolism in high fat and control diet animals using 13C glucose and 13C glutamine tracers.

It is expected that this project will lead to multiple novel findings connecting the metabolic syndrome to cancer. In this project we will focus on metabolic states to explain the connection between obesity and diabetes and the observed increase of cancer risk and progression. We believe that metabolite concentrations and metabolic fluxes integrated with the cellular phenotype will reveal concepts to understand and prevent in the final consequence the increased cancer risk and progression in diabetic and obese people.

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