title: Metabolic origins of spatial organization in the tumor microenvironment.
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.
authors.affiliation: 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.|Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY 10003.
authors.forename: Carlos
authors.initials: C
authors.lastname: Carmona-Fontaine
authors.affiliation: Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Maxime
authors.identifier: 0000-0002-1377-6727
authors.initials: M
authors.lastname: Deforet
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.|Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland.|Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland.
authors.forename: Leila
authors.initials: L
authors.lastname: Akkari
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; carlos.carmona-fontaine@nyu.edu thompsonc@mskcc.org xavierj@mskcc.org.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.|Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland.|Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
authors.affiliation: 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.
authors.forename: Joao B
authors.initials: JB
authors.lastname: Xavier
mesh_terms: D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004734:Energy Metabolism; D005110:Extracellular Space / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D019344:Lactic Acid; D010100:Oxygen
keywords: cancer metabolism; morphogens; positional information; tumor microenvironment; tumor-associated macrophages