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

ABSTRACT: Ly6Chi monocytes massively infiltrate the CRC-tumors by virtue of their CCR2 expression and further mature into Ly6CloF4/80hi CD64hiMHCII+ TAM upon tumor progression. We demonstrated that TAM-deficient tumors display impaired tumor-growth via alternation of the ECM morphology, structure and composition. Using advanced high-resolution optical imaging to visualize the tumoral-ECM macromolecule network together with transcriptomic and proteomic approaches we unraveled that TAM play critical role in the deposition, linearization and cross-linking of collagenous ECM. Remarkably, we show that cues embedded in ECM by TAM-mediated remodeling activity promote tumor cell proliferation in vitro and orthotopic tumor development in vivo. Abnormal remodeling of the extracellular matrix (ECM) structural and compositional is a hallmark of many cancers. While tumor associated macrophages (TAM) are considered pivotal players in mounting pro-tumoral functions, their role in tumor-ECM remodeling remains largely ambiguous. We found that TAM-deficient CRC tumors established in Ccr2-/- mice exhibited attenuated growth. Advanced molecular imaging revealed that the enhanced deposition, linearization and cross-linking of collagen fibers typical to tumor growth were absent in the Ccr2-/- tumors. Integrating transcriptomic and proteomic approaches we defined a TAM signature of ECM remodeling enzymes, structural and affiliated proteins involved with the synthesis and assembly of collagen. 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. 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 indicating that TAM have a critical role in priming pathological ECM cues.

ORGANISM(S): Mus musculus

PROVIDER: GSE67953 | GEO | 2016/09/15

SECONDARY ACCESSION(S): PRJNA281359

REPOSITORIES: GEO