title: Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Susumu
authors.initials: S
authors.lastname: Hirabayashi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Baranski
authors.forename: Ross L
authors.initials: RL
authors.lastname: Cagan
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D059305:Diet, High-Fat; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D051155:Wnt1 Protein / Q000378:metabolism*
chemical_list: D004040:Dietary Carbohydrates; D029721:Drosophila Proteins; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose
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