Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer

被引:34
作者
Lee, Mary [1 ]
Chen, George T. [2 ]
Puttock, Eric [1 ]
Wang, Kehui [3 ,4 ]
Edwards, Robert A. [3 ,4 ]
Waterman, Marian L. [2 ,4 ,5 ]
Lowengrub, John [1 ,4 ,5 ,6 ]
机构
[1] Univ Calif Irvine, Dept Math, Irvine, CA 92717 USA
[2] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA
[3] Univ Calif Irvine, Dept Pathol, Sch Med, Irvine, CA 92717 USA
[4] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA USA
[5] Univ Calif Irvine, Ctr Complex Biol Syst, Irvine, CA USA
[6] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA USA
基金
美国国家科学基金会;
关键词
glycolysis; spatial pattern; tumor metabolism; Warburg effect; Wnt signaling; PYRUVATE-DEHYDROGENASE KINASE; AEROBIC GLYCOLYSIS; SYMBIOSIS; ANGIOGENESIS; GROWTH; RESISTANCE; EXPRESSION; TARGET; SWITCH; CELLS;
D O I
10.15252/msb.20167386
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
Cell-intrinsic metabolic reprogramming is a hallmark of cancer that provides anabolic support to cell proliferation. How reprogramming influences tumor heterogeneity or drug sensitivities is not well understood. Here, we report a self-organizing spatial pattern of glycolysis in xenograft colon tumors where pyruvate dehydrogenase kinase (PDK1), a negative regulator of oxidative phosphorylation, is highly active in clusters of cells arranged in a spotted array. To understand this pattern, we developed a reaction- diffusion model that incorporates Wnt signaling, a pathway known to upregulate PDK1 and Warburg metabolism. Partial interference with Wnt alters the size and intensity of the spotted pattern in tumors and in the model. The model predicts that Wnt inhibition should trigger an increase in proteins that enhance the range of Wnt ligand diffusion. Not only was this prediction validated in xenograft tumors but similar patterns also emerge in radiochemotherapy-treated colorectal cancer. The model also predicts that inhibitors that target glycolysis or Wnt signaling in combination should synergize and be more effective than each treatment individually. We validated this prediction in 3D colon tumor spheroids.
引用
收藏
页数:20
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