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:	EN
Published:	Nature Portfolio 2018
Subjects:	Medicine R Science Q
Online Access:	https://doaj.org/article/b8b1173131934a50bf33d3f5f39499ac
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spelling	oai:doaj.org-article:b8b1173131934a50bf33d3f5f39499ac2021-12-02T15:08:02ZShift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3D microtumors10.1038/s41598-018-27266-82045-2322https://doaj.org/article/b8b1173131934a50bf33d3f5f39499ac2018-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-27266-8https://doaj.org/toc/2045-2322Abstract 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.Manjulata SinghKatsuhiko WaritaTomoko WaritaJames R. FaederRobin E. C. LeeShilpa SantZoltán N. OltvaiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	shift from stochastic to spatially-ordered expression of serine-glycine synthesis enzymes in 3d microtumors
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/b8b1173131934a50bf33d3f5f39499ac
work_keys_str_mv	AT manjulatasingh shiftfromstochastictospatiallyorderedexpressionofserineglycinesynthesisenzymesin3dmicrotumors AT katsuhikowarita shiftfromstochastictospatiallyorderedexpressionofserineglycinesynthesisenzymesin3dmicrotumors AT tomokowarita shiftfromstochastictospatiallyorderedexpressionofserineglycinesynthesisenzymesin3dmicrotumors AT jamesrfaeder shiftfromstochastictospatiallyorderedexpressionofserineglycinesynthesisenzymesin3dmicrotumors AT robineclee shiftfromstochastictospatiallyorderedexpressionofserineglycinesynthesisenzymesin3dmicrotumors AT shilpasant shiftfromstochastictospatiallyorderedexpressionofserineglycinesynthesisenzymesin3dmicrotumors AT zoltannoltvai shiftfromstochastictospatiallyorderedexpressionofserineglycinesynthesisenzymesin3dmicrotumors
_version_	1718388275303940096

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

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