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.
Highlights
Cell-intrinsic metabolic reprogramming is a hallmark of cancer that provides anabolic support to cell proliferation
To investigate metabolic changes within the tumor, 5.0- to 6.0-lm serial sections of formalinfixed, paraffin-embedded tumor were probed with antisera specific for phosphorylated PDH as an indicator of PDK activity, and lymphoid enhancer factor-1 (LEF-1), a Wnt signaling transcription factor and Wnt target gene (Hovanes et al, 2001)
Since it is known that lactate, the secreted by-product of glycolytic cells, can be imported into neighboring cells for use as an oxidative phosphorylation (OXPHOS) metabolic fuel, this pattern points to a potential symbiotic spatial relationship between these two cell populations, a metabolic relationship proposed by other groups studying cancer metabolism (Sonveaux et al, 2008; Pavlides et al, 2009)—glycolytic cells that are localized in distinct regions uptake glucose and produce metabolic fuel such as lactate for surrounding oxidative cells, a mode of sharing and metabolic distribution
Summary
Cell-intrinsic metabolic reprogramming is a hallmark of cancer that provides anabolic support to cell proliferation. 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. The model predicts that Wnt inhibition should trigger an increase in proteins that enhance the range of Wnt ligand diffusion Was this prediction validated in xenograft tumors but similar patterns emerge in radiochemotherapy-treated colorectal cancer.
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