Metabolic origins of spatial organization in the tumor microenvironment.

Détails

Ressource 1Télécharger: pnas.201700600.pdf (20998.15 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_4F0B877B8084
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Metabolic origins of spatial organization in the tumor microenvironment.
Périodique
Proceedings of the National Academy of Sciences of the United States of America
Auteur(s)
Carmona-Fontaine C., Deforet M., Akkari L., Thompson C.B., Joyce J.A., Xavier J.B.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Statut éditorial
Publié
Date de publication
14/03/2017
Peer-reviewed
Oui
Volume
114
Numéro
11
Pages
2934-2939
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity.

Mots-clé
Cell Line, Tumor, Cluster Analysis, Energy Metabolism, Extracellular Space/metabolism, Gene Expression Profiling, Humans, Hypoxia/metabolism, Lactic Acid/metabolism, MAP Kinase Signaling System, Macrophages/metabolism, Macrophages/pathology, Neoplasms/genetics, Neoplasms/metabolism, Neoplasms/pathology, Neovascularization, Pathologic/genetics, Neovascularization, Pathologic/metabolism, Oxygen/metabolism, Phenotype, Transcriptome, Tumor Microenvironment/genetics, cancer metabolism, morphogens, positional information, tumor microenvironment, tumor-associated macrophages
Pubmed
Web of science
Open Access
Oui
Création de la notice
07/03/2017 19:49
Dernière modification de la notice
20/08/2019 15:04
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