Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors

Abstract Cell-to-cell differences in protein expression in normal tissues and tumors are a common phenomenon, but the underlying principles that govern this heterogeneity are largely unknown. Here, we show that in monolayer cancer cell-line cultures, the expression of the five metabolic enzymes of s...

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Main Authors: Manjulata Singh, Katsuhiko Warita, Tomoko Warita, James R. Faeder, Robin E. C. Lee, Shilpa Sant, Zoltán N. Oltvai
Format: Article
Language:English
Published: Nature Portfolio 2018-06-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-018-27266-8
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author Manjulata Singh
Katsuhiko Warita
Tomoko Warita
James R. Faeder
Robin E. C. Lee
Shilpa Sant
Zoltán N. Oltvai
author_facet Manjulata Singh
Katsuhiko Warita
Tomoko Warita
James R. Faeder
Robin E. C. Lee
Shilpa Sant
Zoltán N. Oltvai
author_sort Manjulata Singh
collection DOAJ
description Abstract Cell-to-cell differences in protein expression in normal tissues and tumors are a common phenomenon, but the underlying principles that govern this heterogeneity are largely unknown. Here, we show that in monolayer cancer cell-line cultures, the expression of the five metabolic enzymes of serine-glycine synthesis (SGS), including its rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), displays stochastic cell-to-cell variation. By contrast, in cancer cell line-derived three-dimensional (3D) microtumors PHGDH expression is restricted to the outermost part of the microtumors’ outer proliferative cell layer, while the four other SGS enzymes display near uniform expression throughout the microtumor. A mathematical model suggests that metabolic stress in the microtumor core activates factors that restrict PHGDH expression. Thus, intracellular enzyme expression in growing cell ecosystems can shift to spatially ordered patterns in 3D structured environments due to emergent cell-cell communication, with potential implications for the design of effective anti-metabolic cancer therapies.
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spelling doaj.art-b8b1173131934a50bf33d3f5f39499ac2022-12-21T19:26:12ZengNature PortfolioScientific Reports2045-23222018-06-018111210.1038/s41598-018-27266-8Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumorsManjulata Singh0Katsuhiko Warita1Tomoko Warita2James R. Faeder3Robin E. C. Lee4Shilpa Sant5Zoltán N. Oltvai6Department of Pharmaceutical Sciences, School of Pharmacy, University of PittsburghDepartment of Pathology, School of Medicine, University of PittsburghDepartment of Pathology, School of Medicine, University of PittsburghDepartment of Computational & Systems Biology, School of Medicine, University of PittsburghDepartment of Computational & Systems Biology, School of Medicine, University of PittsburghDepartment of Pharmaceutical Sciences, School of Pharmacy, University of PittsburghDepartment of Pathology, School of Medicine, University of PittsburghAbstract Cell-to-cell differences in protein expression in normal tissues and tumors are a common phenomenon, but the underlying principles that govern this heterogeneity are largely unknown. Here, we show that in monolayer cancer cell-line cultures, the expression of the five metabolic enzymes of serine-glycine synthesis (SGS), including its rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), displays stochastic cell-to-cell variation. By contrast, in cancer cell line-derived three-dimensional (3D) microtumors PHGDH expression is restricted to the outermost part of the microtumors’ outer proliferative cell layer, while the four other SGS enzymes display near uniform expression throughout the microtumor. A mathematical model suggests that metabolic stress in the microtumor core activates factors that restrict PHGDH expression. Thus, intracellular enzyme expression in growing cell ecosystems can shift to spatially ordered patterns in 3D structured environments due to emergent cell-cell communication, with potential implications for the design of effective anti-metabolic cancer therapies.https://doi.org/10.1038/s41598-018-27266-8
spellingShingle Manjulata Singh
Katsuhiko Warita
Tomoko Warita
James R. Faeder
Robin E. C. Lee
Shilpa Sant
Zoltán N. Oltvai
Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors
Scientific Reports
title Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors
title_full Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors
title_fullStr Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors
title_full_unstemmed Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors
title_short Shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors
title_sort shift from stochastic to spatially ordered expression of serine glycine synthesis enzymes in 3d microtumors
url https://doi.org/10.1038/s41598-018-27266-8
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