Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer. Issue 2 (9th February 2017) - Lee, Mary
Abstract: 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. Synopsis: A self‐organizing spotted pattern of glycolysis is discovered in xenograft colon tumors and is consistent with a Turing reaction–diffusion system. Model predictions of gene expression and therapy are validated and reveal synergistic outcomes by targeting Wnt and the glycolytic cell population. Clusters of cells (spots) with high pyruvate dehydrogenase kinase (PDK) activity are observed in colon xenografts indicating a heterogeneous pattern of glycolytic activity. A 3D Turing reaction–diffusion model is developed that incorporates Wnt signaling, a pathway known to upregulate PDK1 and Warburg metabolism and recapitulates the spotted patterns. The model predicts that partial inhibition of Wnt signaling increases the levels of regulators that enhance the range of Wnt ligand diffusion; this is validated in xenograft tumors. Similar effects are found in radiochemotherapy‐treated colorectal cancer patients. Model predictions of synergism between inhibitors of glycolysis and Wnt signaling are validated in 3D colon tumor spheroids. Abstract : A self‐organizing spotted pattern of glycolysis is discovered in xenograft colon tumors and is consistent with a Turing reaction–diffusion system. Model predictions of gene expression and therapy are validated and reveal synergistic outcomes by targeting Wnt and the glycolytic cell population.