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A mechanistic modeling framework reveals the key principles underlying tumor metabolism

While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the n...

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Autores principales: Tripathi, Shubham, Park, Jun Hyoung, Pudakalakatti, Shivanand, Bhattacharya, Pratip K., Kaipparettu, Benny Abraham, Levine, Herbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870510/
https://www.ncbi.nlm.nih.gov/pubmed/35148308
http://dx.doi.org/10.1371/journal.pcbi.1009841
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author Tripathi, Shubham
Park, Jun Hyoung
Pudakalakatti, Shivanand
Bhattacharya, Pratip K.
Kaipparettu, Benny Abraham
Levine, Herbert
author_facet Tripathi, Shubham
Park, Jun Hyoung
Pudakalakatti, Shivanand
Bhattacharya, Pratip K.
Kaipparettu, Benny Abraham
Levine, Herbert
author_sort Tripathi, Shubham
collection PubMed
description While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive heterogeneity with respect to the presentation of the Warburg effect. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. Next, we report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer.
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spelling pubmed-88705102022-02-25 A mechanistic modeling framework reveals the key principles underlying tumor metabolism Tripathi, Shubham Park, Jun Hyoung Pudakalakatti, Shivanand Bhattacharya, Pratip K. Kaipparettu, Benny Abraham Levine, Herbert PLoS Comput Biol Research Article While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive heterogeneity with respect to the presentation of the Warburg effect. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. Next, we report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer. Public Library of Science 2022-02-11 /pmc/articles/PMC8870510/ /pubmed/35148308 http://dx.doi.org/10.1371/journal.pcbi.1009841 Text en © 2022 Tripathi et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tripathi, Shubham
Park, Jun Hyoung
Pudakalakatti, Shivanand
Bhattacharya, Pratip K.
Kaipparettu, Benny Abraham
Levine, Herbert
A mechanistic modeling framework reveals the key principles underlying tumor metabolism
title A mechanistic modeling framework reveals the key principles underlying tumor metabolism
title_full A mechanistic modeling framework reveals the key principles underlying tumor metabolism
title_fullStr A mechanistic modeling framework reveals the key principles underlying tumor metabolism
title_full_unstemmed A mechanistic modeling framework reveals the key principles underlying tumor metabolism
title_short A mechanistic modeling framework reveals the key principles underlying tumor metabolism
title_sort mechanistic modeling framework reveals the key principles underlying tumor metabolism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870510/
https://www.ncbi.nlm.nih.gov/pubmed/35148308
http://dx.doi.org/10.1371/journal.pcbi.1009841
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