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

Cell. 2013 Aug 1;154(3):664-75. doi: 10.1016/j.cell.2013.06.030.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Diet, High-Fat
  • Dietary Carbohydrates / administration & dosage*
  • Disease Models, Animal*
  • Drosophila / metabolism*
  • Drosophila Proteins / metabolism*
  • Glucose / metabolism
  • Humans
  • Insulin Resistance*
  • Neoplasms / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction*
  • Wnt1 Protein / metabolism*


  • Dietary Carbohydrates
  • Drosophila Proteins
  • Wnt1 Protein
  • wg protein, Drosophila
  • Phosphatidylinositol 3-Kinases
  • Glucose