GSE107053
Tumor-associated macrophages derived from circulating inflammatory monocytes degrade collagen through cellular uptake
Physiologic turnover of interstitial collagen is mediated by a sequential pathway, in which collagen is fragmented by pericellular collagenases, endocytosed by specific collagen receptors, and routed to lysosomes for degradation by lysosomal cathepsins. Here, we used intravital microscopy to investigate if malignant tumors, which are characterized by high rates of extracellular matrix turnover, utilize a similar collagen degradation pathway. Tumors of epithelial, mesenchymal, or neural crest origin all displayed vigorous endocytic collagen degradation with an abundance of cells engaged in this process. These cells were identified as tumor-associated macrophage (TAM)-like cells that degraded collagen in a mannose receptor-dependent manner. Accordingly, increased intra-tumoral collagen was observed in mannose receptor-deficient mice. Whole transcriptome profiling uncovered a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies revealed that collagen-degrading TAMs originated from circulating CCR2+ monocytes. The study identifies a novel function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation. Overall design: Quantification of RNA expression in whole Lewis lung carcinomas (total tumor) and in three different cell types isolated from Lewis lung carcinomas. Lewis lung carcinoma cells (LLC), Fibroblasts and M2 tumor-associated macrophages (TAM).