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Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):2934-2939. doi: 10.1073/pnas.1700600114. Epub 2017 Feb 28.

Metabolic origins of spatial organization in the tumor microenvironment.

Author information

1
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; carlos.carmona-fontaine@nyu.edu thompsonc@mskcc.org xavierj@mskcc.org.
2
Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY 10003.
3
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
4
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
5
Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland.
6
Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland.
7
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; carlos.carmona-fontaine@nyu.edu thompsonc@mskcc.org xavierj@mskcc.org.

Abstract

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.

KEYWORDS:

cancer metabolism; morphogens; positional information; tumor microenvironment; tumor-associated macrophages

PMID:
28246332
PMCID:
PMC5358370
DOI:
10.1073/pnas.1700600114
[Indexed for MEDLINE]
Free PMC Article

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