Cellular limitation of enzymatic capacity explains glutamine addiction in cancers
Preprint, 2022

Metabolism within the tumor microenvironment, where a complex mixture of different cell types resides in a nutrient-deprived surrounding, is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells’ preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common belief that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified a total of 233 potential metabolites that could support collaboration between cancer cells and cancer associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme constrained models for accurate prediction of metabolism in cells and tumor microenvironments.

tumor microenvironment

cancer

Genome-scale metabolic modeling

amino acid metabolism

cancer-associated fibroblasts

glutamine addiction

metabolism

Författare

Johan Gustafsson

Chalmers, Biologi och bioteknik, Systembiologi

Fariba Roshanzamir

Chalmers, Biologi och bioteknik, Systembiologi

Anders Hagnestål

Hagnesia AB

Jonathan Robinson

Chalmers, Biologi och bioteknik, Systembiologi

Jens B Nielsen

Chalmers, Biologi och bioteknik, Systembiologi

Ämneskategorier

Cellbiologi

Biomedicinsk laboratorievetenskap/teknologi

Bioinformatik (beräkningsbiologi)

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

Styrkeområden

Livsvetenskaper och teknik (2010-2018)

DOI

10.1101/2022.02.08.479584

Mer information

Skapat

2022-05-03