Emergent behaviour and phase transitions in spatially distributed multi-cellular metabolic networks
| Autor: | Narayanankutty, K., Pereiro-Morejon, J. A., Ferrero, A., Onesto, V., Forciniti, S., del Mercato, L. L., Mulet, R., De Martino, A., Tourigny, D. S., De Martino, D. |
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| Rok vydání: | 2024 |
| Předmět: | |
| Druh dokumentu: | Working Paper |
| Popis: | Overflow metabolism is a ubiquitous phenomenon whereby cells in aerobic conditions excrete byproducts of glycolysis, such as lactate or acetate, into the medium in a seemingly wasteful and polluting fashion. Whilst overflow may confer microbes a fitness advantage by allowing them to overcome a finite oxidative capacity, its occurrence in higher organisms is harder to assess. Important insight was however obtained in recent experiments conducted at single-cell resolution, which revealed that accumulation of overflow products in tumor cell cultures known as the Warburg effect arises from imbalances in the dynamic and heterogeneous inter-cellular exchange network through which cells collectively regulate the microenvironment. Here we provide a quantitative characterization of this scenario by integrating metabolic network modeling with diffusion constraints, statistical physics theory and single-cell experimental flux data. On the theoretical side, we clarify how diffusion-limited exchanges shape the space of viable metabolic states of a multi-cellular system. Specifically, a phase transition from a balanced network of exchanges to an unbalanced overflow regime occurs as the mean cellular glucose and oxygen uptakes vary while single-cell metabolic phenotypes are highly heterogeneous around this transition. We then show that time-resolved data from human tumor-stroma cell co-cultures consistently map to this crossover region, supporting the idea that environmental deterioration reflects a failure of coordination among recurrently interacting cells. In summary, our findings suggest that, rather than deriving from multiple independent cell-autonomous processes, environmental control is an emergent feature of multi-cellular systems. Comment: Main(14 pages)+ supporting information(14 pages). Comments are welcome |
| Databáze: | arXiv |
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