Metabolic coordination and phase transitions in spatially distributed multi-cellular systems

TL;DR

This paper models how spatial metabolic interactions among cells lead to phase transitions from balanced to overflow states, revealing environmental control as an emergent property in multi-cellular systems.

Contribution

It introduces a quantitative framework combining spatial metabolic modeling and statistical physics to explain overflow metabolism as a phase transition driven by inter-cellular exchange imbalances.

Findings

Diffusion-limited exchanges determine multi-cellular metabolic states.

A phase transition occurs with varying glucose and oxygen uptake rates.

Overflow metabolism results from failure of inter-cellular metabolic coordination.

Abstract

During overflow metabolism, cells excrete glycolytic byproducts when growing under aerobic conditions in a seemingly wasteful fashion. While potentially advantageous for microbes with finite oxidative capacity, its role in higher organisms is harder to assess. Recent single-cell experiments suggest overflow metabolism arises due to imbalances in inter-cellular exchange networks. We quantitatively characterize this scenario by integrating spatial metabolic modeling with tools from statistical physics and experimental single-cell flux data. Our results provide a theoretical demonstration of how diffusion-limited exchanges shape the space of accessible multi-cellular metabolic states. Specifically, a phase transition from a balanced network of exchanges to an unbalanced, overflow regime occurs as mean glucose and oxygen uptake rates vary. Heterogeneous single-cell metabolic phenotypes occur near this transition. Time-resolved tumor-stroma co-culture data support the idea that overflow metabolism stems from failure of inter-cellular metabolic coordination. In summary, environmental control is an emergent multi-cellular property, rather than a cell-autonomous effect.