Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer
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 co...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2017-02-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.20167386 |
| _version_ | 1797225451756716032 |
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| author | Mary Lee George T Chen Eric Puttock Kehui Wang Robert A Edwards Marian L Waterman John Lowengrub |
| author_facet | Mary Lee George T Chen Eric Puttock Kehui Wang Robert A Edwards Marian L Waterman John Lowengrub |
| author_sort | Mary Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T03:11:22Z |
| format | Article |
| id | doaj.art-e5b2efb5e8c447a9a86b5fe339cb92c0 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-04-24T14:09:14Z |
| publishDate | 2017-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-e5b2efb5e8c447a9a86b5fe339cb92c02024-04-03T09:38:21ZengSpringer NatureMolecular Systems Biology1744-42922017-02-01132n/an/a10.15252/msb.20167386Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancerMary Lee0George T Chen1Eric Puttock2Kehui Wang3Robert A Edwards4Marian L Waterman5John Lowengrub6Department of Mathematics University of California, Irvine Irvine CA USADepartment of Microbiology and Molecular Genetics University of California, Irvine Irvine CA USADepartment of Mathematics University of California, Irvine Irvine CA USADepartment of Pathology School of Medicine University of California, Irvine Irvine CA USADepartment of Pathology School of Medicine University of California, Irvine Irvine CA USADepartment of Microbiology and Molecular Genetics University of California, Irvine Irvine CA USADepartment of Mathematics University of California, Irvine Irvine CA USAAbstract 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.https://doi.org/10.15252/msb.20167386glycolysisspatial patterntumor metabolismWarburg effectWnt signaling |
| spellingShingle | Mary Lee George T Chen Eric Puttock Kehui Wang Robert A Edwards Marian L Waterman John Lowengrub Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer Molecular Systems Biology glycolysis spatial pattern tumor metabolism Warburg effect Wnt signaling |
| title | Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer |
| title_full | Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer |
| title_fullStr | Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer |
| title_full_unstemmed | Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer |
| title_short | Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer |
| title_sort | mathematical modeling links wnt signaling to emergent patterns of metabolism in colon cancer |
| topic | glycolysis spatial pattern tumor metabolism Warburg effect Wnt signaling |
| url | https://doi.org/10.15252/msb.20167386 |
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