Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake
Daniel Hargbøl Madsen,
Henrik Jessen Jürgensen,
Majken Storm Siersbæk,
Dorota Ewa Kuczek,
Loretta Grey Cloud,
Shihui Liu,
Niels Behrendt,
Lars Grøntved,
Roberto Weigert,
Thomas Henrik Bugge
Affiliations
Daniel Hargbøl Madsen
Proteases and Tissue Remodeling Section , Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Henrik Jessen Jürgensen
Proteases and Tissue Remodeling Section , Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Majken Storm Siersbæk
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
Dorota Ewa Kuczek
Center for Cancer Immune Therapy, Department of Haematology, Copenhagen University Hospital, 2730 Herlev, Denmark
Loretta Grey Cloud
Proteases and Tissue Remodeling Section , Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Shihui Liu
Proteases and Tissue Remodeling Section , Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Niels Behrendt
The Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark
Lars Grøntved
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
Roberto Weigert
Intracellular Membrane Trafficking Unit , Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Thomas Henrik Bugge
Proteases and Tissue Remodeling Section , Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Physiologic turnover of interstitial collagen is mediated by a sequential pathway in which collagen is fragmented by pericellular collagenases, endocytosed by collagen receptors, and routed to lysosomes for degradation by cathepsins. Here, we use 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 display vigorous endocytic collagen degradation. The cells engaged in this process are identified as tumor-associated macrophage (TAM)-like cells that degrade collagen in a mannose receptor-dependent manner. Accordingly, mannose-receptor-deficient mice display increased intratumoral collagen. Whole-transcriptome profiling uncovers a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies reveal that collagen-degrading TAMs originate from circulating CCR2+ monocytes. This study identifies a function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation.
