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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2018
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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) |
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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 |
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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 |
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1718388275303940096 |