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Can metabolic states induced by diabetes and obesity promote cancer? (MetabolismConnect)
Start date: Oct 1, 2013, End date: Sep 30, 2017 PROJECT  FINISHED 

Continuous research on cancer has unraveled genetic alterations and subsequently signal transduction pathways changed in a cancer cell, thereby it emerged that many of the genetic factors commonly altered in cancer cells often 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 a major question in the field. The hypothesis that certain metabolic states can precondition a cell for cancer is supported by epidemiological studies showing that patients suffering from diabetes or obesity have an increased risk to develop cancer and an increased cancer mortality rate.We propose to elucidate whether certain metabolic states promote liver cancer, which is in 30% of the cases associated with diabetes and obesity. We will measure metabolite concentrations and metabolic fluxes in tumorigenic versus non-malignant liver cells in vitro, to systematically identify metabolic states that are sufficient to drive an oncogenic transformation in the liver. Subsequently, we will map them in vivo onto metabolic states quantified in a diet and carcinogen induced mouse model, with the final goal to unravel the causal link between the increased liver cancer risk and the metabolic syndrome. Elucidating this metabolic interface will provide a mechanistic understanding of tumor initiating events in patients suffering from the metabolic syndrome. It will subsequently lead to new therapeutic strategies to prevent increased tumor events and cancer driven mortality rates in such patients.

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