Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake

Abstract

Summary 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 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. The cells engaged in this process were identified as tumor-associated macrophage (TAM)-like cells that degraded collagen in a mannose receptor-dependent manner. Accordingly, mannose receptor-deficient mice displayed increased intra-tumoral collagen. 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 function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation.

Monocyte heterogeneity and functions in cancer

“…Densely cross‐linked fibrin provides a scaffold for metastatic tumor cell invasion and is associated with CD14 expression and disease progression in non‐small lung cancer patients . Mϕs derived from CCR2 + monocytes can directly degrade the ECM within tumors by endocytosing deposited collagen . Additional studies are needed to better understand how monocytes contribute to the composition and organization of tumor ECM, and whether ECM‐derived signals regulate monocyte fate in cancer.…”

Getting TANned: How the tumor microenvironment drives neutrophil recruitment

“…Tumor‐defying and antimetastatic property has also been attributed to MMP8, most likely derived from TANs, in murine melanoma and lung cancer models where MMP8 increased adhesion of tumor cells to ECM proteins and reduced tumor invasiveness . Collagen fragments, most likely derived from various MMP actions, are further degraded through endocytic pathways by a subset of TAMs, originating from CCR2+ monocytes in a mouse lung carcinoma model . Therefore, the dynamics of TAM/TAN‐mediated ECM remodeling dictate the fate of tumor progression in vivo.…”

“…148 Collagen fragments, most likely derived from various MMP actions, are further degraded through endocytic pathways by a subset of TAMs, originating from CCR2+ monocytes in a mouse lung carci-noma model. 153 Therefore, the dynamics of TAM/TAN-mediated ECM remodeling dictate the fate of tumor progression in vivo.…”

Integratedin silicoand 3Din vitromodel of macrophage migration in response to physical and chemical factors in the tumor microenvironment

“…Macrophages remodel extracellular matrix (ECM) through matrix metalloproteinases (MMP) which degrade collagen and create tracks for tumor cells to migrate [31,32]. Such tracks also enable macrophages to migrate toward and interact with other cells in the TME to support tumor progression, for example by their contact-dependent support of the epithelial-to-mesenchymal transition (EMT) of tumor cell aggregates [33], or their contact with the endothelium to increase its permeability to intravasating tumor cells [34].…”