Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer.
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.
Department of Mathematics, University of California, Irvine, Irvine, CA, USA.
Mary
M
Lee
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA.
George T
GT
Chen
Department of Mathematics, University of California, Irvine, Irvine, CA, USA.
Eric
E
Puttock
Department of Pathology, School of Medicine, University of California, Irvine, Irvine, CA, USA.|Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA.
Kehui
K
Wang
Department of Pathology, School of Medicine, University of California, Irvine, Irvine, CA, USA.|Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA.
Robert A
RA
Edwards
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA marian.waterman@uci.edu jlowengr@uci.edu.|Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA.|Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA.
Marian L
ML
Waterman
Department of Mathematics, University of California, Irvine, Irvine, CA, USA marian.waterman@uci.edu jlowengr@uci.edu.|Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA.|Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA.|Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA.
John
0000-0003-1759-0900
J
Lowengrub
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D051379:Mice; D008962:Models, Theoretical; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases
Warburg effect; Wnt signaling; glycolysis; spatial pattern; tumor metabolism