title: Tumor macrophages are pivotal constructors of tumor collagenous matrix.
abstract: Tumor-associated macrophages (TAMs) promote tumor development, invasion, and dissemination by various mechanisms. In this study, using an orthotopic colorectal cancer (CRC) model, we found that monocyte-derived TAMs advance tumor development by the remodeling of its extracellular matrix (ECM) composition and structure. Unbiased transcriptomic and proteomic analyses of (a) TAM-abundant and -deficient tumor tissues and (b) sorted tumor-associated and -resident colonic macrophage subpopulations defined a distinct TAM-induced ECM molecular signature composed of an ensemble of matricellular proteins and remodeling enzymes they provide to the tumor microenvironment. Remarkably, many of these ECM proteins are specifically increased in human CRC versus healthy colon. Specifically, we demonstrate that although differentiating into TAMs, monocytes up-regulate matrix-remodeling programs associated with the synthesis and assembly of collagenous ECM, specifically collagen types I, VI, and XIV. This finding was further established by advanced imaging showing that TAMs instruct the deposition, cross-linking, and linearization of collagen fibers during tumor development, especially at areas of tumor invasiveness. Finally, we show that cancer-associated fibroblasts are significantly outnumbered by TAMs in this model and that their expression of collagen XIV and I is reduced by TAM deficiency. Here, we outline a novel TAM protumoral function associated with building of the collagenous ECM niche.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Afik
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Zigmond
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Milena
authors.identifier: 0000-0001-5113-7320
authors.initials: M
authors.lastname: Vugman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Mordehay
authors.identifier: 0000-0002-6092-2133
authors.initials: M
authors.lastname: Klepfish
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Elee
authors.identifier: 0000-0003-3057-5393
authors.initials: E
authors.lastname: Shimshoni
authors.affiliation: Bioinformatics Unit, George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Anjana
authors.identifier: 0000-0001-5279-9211
authors.initials: A
authors.lastname: Shenoy
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Elad
authors.identifier: 0000-0001-5851-052X
authors.initials: E
authors.lastname: Bassat
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Zamir
authors.identifier: 0000-0003-0195-6138
authors.initials: Z
authors.lastname: Halpern
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Tamar
authors.identifier: 0000-0002-9526-197X
authors.initials: T
authors.lastname: Geiger
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Irit
authors.identifier: 0000-0001-5595-5515
authors.initials: I
authors.lastname: Sagi
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel chenv@tlvmc.gov.il irit.sagi@weizmann.ac.il.
authors.forename: Chen
authors.initials: C
authors.lastname: Varol
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D024022:Fibrillar Collagens / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D040901:Proteomics; D054390:Receptors, CCR2 / Q000172:deficiency / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: C515335:Ccr2 protein, mouse; D016326:Extracellular Matrix Proteins; D024022:Fibrillar Collagens; D054390:Receptors, CCR2