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Metabolism and Cell Growth

Susumu Hirabayashi

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Medical Research Council (MRC)
The prevalence of obesity is increasing globally. Accumulating epidemiological evidence implies that obesity—associated with insulin resistance—is a risk factor for several types of cancers. However, a biological basis for the associations between whole-animal metabolism and cancer remain incompletely understood. Using Drosophila, I have developed a model system to study the link between obesity and cancer (Hirabayashi et al. 2013, Cell 154, 664). Feeding Drosophila a high-sucrose diet was previously demonstrated to promote metabolic defects including accumulation of fat, hyperglycemia, increased insulin levels (hyperinsulinemia), insulin resistance, and heart defects, indicating that the simple feeding model recapitulated many of the metabolic features of mammalian obesity. A high-sucrose diet also leads to a striking enhancement of tumour progression in a Ras/Src co-activated Drosophila tumour model. Diet-induced tumour growth has consequences on animal viability, evidenced by the death of most larvae prior to pupariation. This synergistic, diet-plus-cancer dependent mortality is an ideal phenotype for genetic screens designed to identify regulators of obesity-dependent tumourigenesis. I will further utilize this Drosophila diet-enhanced tumour model as useful whole-animal systems to better understand the mechanistic links between diet-induced metabolic defects and tumour progression. Conversely, cancer progression induces metabolic changes including cancer-associated cachexia, a wasting syndrome of progressive muscle and adipose tissue loss. Cancer-induced metabolic changes can profoundly influence treatment efficacy and the quality of life for cancer patients. However, the biological mechanism for the cancer-induced metabolic changes are not well understood. Animals with diet-enhanced Ras/Src-tumours possess less fat body (i.e., Drosophila adipose tissue). This metabolic feature recapitulated cachexia-like adipose tissue wasting of cancer patients and is suitable for addressing a complementary question of how tumours affect whole-animal metabolism. Overall, our research goal is to discover and elucidate the biological mechanisms and therapeutic targets involved in the interactions between metabolism and tumour progression in a whole-animal context.

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