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.
Highlights
In nature, most cells exist as part of a cellular ecosystem, whether it is bacterial biofilms, tissue and tumor ecosystems, or highly organized tissue architectures
Without any external stimulus, microtumors derived from select cancer cell lines develop three key hallmarks of tumor progression observed in vivo: increasing microtumor size drives hypoxia and metabolic stress; heterogeneous tumor cells expressing different levels of E-cadherin and vimentin spontaneously emerge; and peripheral cells begin to migrate from the parent tumor
We determined the average cellular expression levels of the serine-glycine synthesis (SGS) enzymes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT), phosphoserine phosphatase (PSPH) and serine hydroxymethyltransferases 1 and 2 (SHMT1, SHMT2) (Fig. 1A) when these cells were propagated in serine and glycine-containing growth medium
Summary
Most cells exist as part of a cellular ecosystem, whether it is bacterial biofilms, tissue and tumor ecosystems, or highly organized tissue architectures. The observed enzyme expression heterogeneity may reflect the tumor cells’ response to signals from their local environment both, due to nutrient- and/or oxygen gradients or due to autocrine- or non-cell autonomous paracrine effects from other tumor cells or non-tumor cell types[7] The influence of these factors on the system-level organization of cell function, including cell metabolism remains only partially understood. Metabolic models suggest that above a threshold ATP and/or biomass production (cell division) rate, cells switch from oxidative phosphorylation (OxPhos) to overflow metabolism (i.e., mixed OxPhos/fermentation)[8,9,10], which could explain the observed differences between rapidly proliferating and slowly dividing sectors of a growing tumor This metabolic reorganization is predicted to involve upregulation of the serine-glycine synthesis and one-carbon metabolism (SGOC) pathways[11] (Fig. 1A). Intracellular enzyme expression in monoclonal cell ecosystems can shift from stochastic to a spatially organized pattern when cells encounter 3D structured microenvironments, in which tight regulation of spatial expression may be limited to rate-limiting enzymes of the metabolic pathways
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