Proteomics

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Tumor-Associated Macrophages Promote Colorectal Tumor Development Through Remodeling of Its Extracellular Matrix


ABSTRACT: Extracellular matrix (ECM) structural and compositional abnormalities are a hallmark of many cancers. Tumor associated macrophages (TAM) are considered pivotal players in mounting pro-tumoral functions; yet, their role in tumor-ECM remodeling remains largely ambiguous. Using an orthotopic murine model of colorectal cancer we defined two major CRC TAM subsets arising from Ly6Chi monocytes recruited in a CCR2-depedent manner. TAM-deficient CRC tumors established Ccr2-/- mice exhibited attenuated growth. Advanced imaging techniques revealed that the enhanced deposition, linearization and cross-linking of collagen fibers typical to tumor growth were absent in the Ccr2-/- tumors. Moreover, the Ccr2-/- tumors displayed altered ECM composition with 348 proteins that were differentially expressed in comparison with WT tumors, among them 46 were ECM related. Integrating transcriptomic and proteomic approaches we defined a TAM signature of ECM remodeling enzymes, structural and affiliated proteins. Specifically, were prominent proteins involved with the synthesis and assembly of collagen type I, IV and XIV. Finally, decellularized 3D ECM fragments extracted from WT tumors, but not from Ccr2-/- tumors or upstream healthy colon, enhanced tumor cell proliferation in vitro and tumor development in the native colonic environment. Collectively, our integrated biophysical-immunologic-omic approaches uncover new mechanistic insights of TAM-mediated remodeling of tumor ECM structure and composition.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Colon, Macrophage

DISEASE(S): Colon Cancer

SUBMITTER: Tamar Geiger  

LAB HEAD: Dr. Tamar Geiger

PROVIDER: PXD002094 | Pride | 2016-09-26

REPOSITORIES: Pride

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Publications

Tumor macrophages are pivotal constructors of tumor collagenous matrix.

Afik Ran R   Zigmond Ehud E   Vugman Milena M   Klepfish Mordehay M   Shimshoni Elee E   Pasmanik-Chor Metsada M   Shenoy Anjana A   Bassat Elad E   Halpern Zamir Z   Geiger Tamar T   Sagi Irit I   Varol Chen C  

The Journal of experimental medicine 20161003 11


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 def  ...[more]

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