Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling.

Cell 2013 Aug;154(3):664-75

Department of Developmental and Regenerative Biology, Annenberg 25-40, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1020, New York, NY 10029, USA.

The risk of specific cancers increases in patients with metabolic dysfunction, including obesity and diabetes. Here, we use Drosophila as a model to explore the effects of diet on tumor progression. Feeding Drosophila a diet high in carbohydrates was previously demonstrated to direct metabolic dysfunction, including hyperglycemia, hyperinsulinemia, and insulin resistance. We demonstrate that high dietary sugar also converts Ras/Src-transformed tissue from localized growths to aggressive tumors with emergent metastases. Whereas most tissues displayed insulin resistance, Ras/Src tumors retained insulin pathway sensitivity, increased the ability to import glucose, and resisted apoptosis. High dietary sugar increased canonical Wingless/Wnt pathway activity, which upregulated insulin receptor gene expression to promote insulin sensitivity. The result is a feed-forward circuit that amplified diet-mediated malignant phenotypes within Ras/Src-transformed tumors. By targeting multiple steps in this circuit with rationally applied drug combinations, we demonstrate the potential of combinatorial drug intervention to treat diet-enhanced malignant tumors.

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http://dx.doi.org/10.1016/j.cell.2013.06.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800019PMC
August 2013
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