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

Manjulata Singh, Katsuhiko Warita, Tomoko Warita, James R. Faeder, Robin E.C. Lee, Shilpa Sant, Zoltán N. Oltvai

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Article number9388
JournalScientific reports
Issue number1
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
We thank A. Vazquez and J.R. Chaillet for comments on the manuscript. Funding for this work was provided in part by NIH grants #R35GM119462 to RECL and #R03EB018575 to SS, and NSF grant #BCSP 1356505 to ZNO.

Publisher Copyright:
© 2018 The Author(s).


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