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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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. Madsen et al. identify a population of tumor-associated macrophages with a distinct matrix catabolic signature as key effectors of collagen turnover during invasive tumor growth. These matrix-degrading macrophages are largely derived from CCR2+ monocytes reprogrammed by the tumor microenvironment and degrade collagen through mannose receptor-dependent cellular uptake.

Original languageEnglish
JournalCell Reports
Volume21
Issue number13
Pages (from-to)3662-3671
ISSN2211-1247
DOIs
Publication statusPublished - 26. Dec 2017

Fingerprint

Macrophages
Tumors
Collagen
Neoplasms
Degradation
Collagen Receptors
Cathepsins
Neural Crest
Gene Expression Profiling
Collagenases
Ablation
Endocytosis

Keywords

  • cancer invasion
  • cathepsins
  • CCR2-derived TAMs
  • collagen endocytosis
  • collagenases
  • endocytic matrix turnover
  • extracellular matrix remodeling
  • M2-polarized macrophages
  • tumor microenvironment
  • tumor-associated macrophages

Cite this

Madsen, Daniel Hargbøl ; Jürgensen, Henrik Jessen ; Siersbæk, Majken Storm ; Kuczek, Dorota Ewa ; Grey Cloud, Loretta ; Liu, Shihui ; Behrendt, Niels ; Grøntved, Lars ; Weigert, Roberto ; Bugge, Thomas Henrik. / Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake. In: Cell Reports. 2017 ; Vol. 21, No. 13. pp. 3662-3671.
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abstract = "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. Madsen et al. identify a population of tumor-associated macrophages with a distinct matrix catabolic signature as key effectors of collagen turnover during invasive tumor growth. These matrix-degrading macrophages are largely derived from CCR2+ monocytes reprogrammed by the tumor microenvironment and degrade collagen through mannose receptor-dependent cellular uptake.",
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Madsen, DH, Jürgensen, HJ, Siersbæk, MS, Kuczek, DE, Grey Cloud, L, Liu, S, Behrendt, N, Grøntved, L, Weigert, R & Bugge, TH 2017, 'Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake', Cell Reports, vol. 21, no. 13, pp. 3662-3671. https://doi.org/10.1016/j.celrep.2017.12.011

Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake. / Madsen, Daniel Hargbøl; Jürgensen, Henrik Jessen; Siersbæk, Majken Storm; Kuczek, Dorota Ewa; Grey Cloud, Loretta; Liu, Shihui; Behrendt, Niels; Grøntved, Lars; Weigert, Roberto; Bugge, Thomas Henrik.

In: Cell Reports, Vol. 21, No. 13, 26.12.2017, p. 3662-3671.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake

AU - Madsen, Daniel Hargbøl

AU - Jürgensen, Henrik Jessen

AU - Siersbæk, Majken Storm

AU - Kuczek, Dorota Ewa

AU - Grey Cloud, Loretta

AU - Liu, Shihui

AU - Behrendt, Niels

AU - Grøntved, Lars

AU - Weigert, Roberto

AU - Bugge, Thomas Henrik

PY - 2017/12/26

Y1 - 2017/12/26

N2 - 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. Madsen et al. identify a population of tumor-associated macrophages with a distinct matrix catabolic signature as key effectors of collagen turnover during invasive tumor growth. These matrix-degrading macrophages are largely derived from CCR2+ monocytes reprogrammed by the tumor microenvironment and degrade collagen through mannose receptor-dependent cellular uptake.

AB - 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. Madsen et al. identify a population of tumor-associated macrophages with a distinct matrix catabolic signature as key effectors of collagen turnover during invasive tumor growth. These matrix-degrading macrophages are largely derived from CCR2+ monocytes reprogrammed by the tumor microenvironment and degrade collagen through mannose receptor-dependent cellular uptake.

KW - cancer invasion

KW - cathepsins

KW - CCR2-derived TAMs

KW - collagen endocytosis

KW - collagenases

KW - endocytic matrix turnover

KW - extracellular matrix remodeling

KW - M2-polarized macrophages

KW - tumor microenvironment

KW - tumor-associated macrophages

U2 - 10.1016/j.celrep.2017.12.011

DO - 10.1016/j.celrep.2017.12.011

M3 - Journal article

C2 - 29281816

AN - SCOPUS:85039941961

VL - 21

SP - 3662

EP - 3671

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 13

ER -