TY - JOUR
T1 - XTransformed drosophila cells evade diet-mediated insulin resistance through wingless signaling
AU - Hirabayashi, Susumu
AU - Baranski, Thomas J.
AU - Cagan, Ross L.
N1 - Funding Information:
We thank J. Diaz, J. Na, J. Pendse, L.P. Musselman, J. Fink, M. Vidal, and current and former Baranski and Cagan lab members for helpful discussions; C.Y. Nien for writing MATLAB scripts for quantitation; Y. Tomer and D. LeRoith for manuscript comments; and A. O’Reilly, M. Simon, D. Bilder, G. Halder, H. Steller, M. Krasnow, A. Dar, and K. Shokat for reagents. We also thank the Bloomington Stock Center, the Vienna Drosophila RNAi Center, and the Developmental Studies Hybridoma Bank for fly strains and antibodies. This research was supported by the National Cancer Institute (grants R01 CA170495 and R01 CA109730 to S.H. and R.L.C. and grant R21 DK069940 to R.L.C. and T.J.B.). R.L.C. and T.J.B. are cofounders of Medros, which uses fly models of human disease for drug development.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84881133805&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.06.030
DO - 10.1016/j.cell.2013.06.030
M3 - Article
C2 - 23911328
AN - SCOPUS:84881133805
SN - 0092-8674
VL - 154
SP - X664-675
JO - Cell
JF - Cell
IS - 3
ER -