Quantitative constraint-based computational model of tumor-to-stroma coupling via lactate shuttle

TL;DR

This paper presents a quantitative computational model demonstrating how lactate shuttling between tumor and stromal cells can create a mutually beneficial metabolic coupling, supporting tumor growth and microenvironment complexity.

Contribution

It introduces a large-scale in silico metabolic model that quantitatively analyzes tumor-stroma coupling via lactate exchange, extending beyond cell-autonomous descriptions.

Findings

Physico-chemical constraints favor lactate shuttle formation.

Metabolic coupling depends on nutrient demands and partitioning.

Synergistic effects are crucial for tumor sustainability.

Abstract

Cancer cells utilize large amounts of ATP to sustain growth, relying primarily on non-oxidative, fermentative pathways for its production. In many types of cancers this leads, even in the presence of oxygen, to the secretion of carbon equivalents (usually in the form of lactate) in the cell's surroundings, a feature known as the Warburg effect. While the molecular basis of this phenomenon are still to be elucidated, it is clear that the spilling of energy resources contributes to creating a peculiar microenvironment for tumors, possibly characterized by a degree of toxicity. This suggests that mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may be active, effectively inducing a mutually beneficial metabolic coupling between aberrant and non-aberrant cells. Here we analyze this scenario through a large-scale in silico metabolic model of interacting human cells. By going beyond the cell-autonomous description, we show that elementary physico-chemical constraints indeed favor the establishment of such a coupling under very broad conditions. The characterization we obtained by tuning the aberrant cell's demand for ATP, amino-acids and fatty acids and/or the imbalance in nutrient partitioning provides quantitative support to the idea that synergistic multi-cell effects play a central role in cancer sustainment.