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Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression.

Publication ,  Journal Article
Maller, O; Drain, AP; Barrett, AS; Borgquist, S; Ruffell, B; Zakharevich, I; Pham, TT; Gruosso, T; Kuasne, H; Lakins, JN; Acerbi, I; Nemkov, T ...
Published in: Nat Mater
April 2021

Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.

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Published In

Nat Mater

DOI

EISSN

1476-4660

Publication Date

April 2021

Volume

20

Issue

4

Start / End Page

548 / 559

Location

England

Related Subject Headings

  • Tumor-Associated Macrophages
  • Stromal Cells
  • Protein-Lysine 6-Oxidase
  • Nanoscience & Nanotechnology
  • Middle Aged
  • Humans
  • Female
  • Collagen
  • Cell Line, Tumor
  • Breast Neoplasms
 

Citation

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Maller, O., Drain, A. P., Barrett, A. S., Borgquist, S., Ruffell, B., Zakharevich, I., … Weaver, V. M. (2021). Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat Mater, 20(4), 548–559. https://doi.org/10.1038/s41563-020-00849-5
Maller, Ori, Allison P. Drain, Alexander S. Barrett, Signe Borgquist, Brian Ruffell, Igor Zakharevich, Thanh T. Pham, et al. “Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression.Nat Mater 20, no. 4 (April 2021): 548–59. https://doi.org/10.1038/s41563-020-00849-5.
Maller O, Drain AP, Barrett AS, Borgquist S, Ruffell B, Zakharevich I, et al. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat Mater. 2021 Apr;20(4):548–59.
Maller, Ori, et al. “Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression.Nat Mater, vol. 20, no. 4, Apr. 2021, pp. 548–59. Pubmed, doi:10.1038/s41563-020-00849-5.
Maller O, Drain AP, Barrett AS, Borgquist S, Ruffell B, Zakharevich I, Pham TT, Gruosso T, Kuasne H, Lakins JN, Acerbi I, Barnes JM, Nemkov T, Chauhan A, Gruenberg J, Nasir A, Bjarnadottir O, Werb Z, Kabos P, Chen Y-Y, Hwang ES, Park M, Coussens LM, Nelson AC, Hansen KC, Weaver VM. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat Mater. 2021 Apr;20(4):548–559.

Published In

Nat Mater

DOI

EISSN

1476-4660

Publication Date

April 2021

Volume

20

Issue

4

Start / End Page

548 / 559

Location

England

Related Subject Headings

  • Tumor-Associated Macrophages
  • Stromal Cells
  • Protein-Lysine 6-Oxidase
  • Nanoscience & Nanotechnology
  • Middle Aged
  • Humans
  • Female
  • Collagen
  • Cell Line, Tumor
  • Breast Neoplasms