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

Maller, Ori ; Drain, Allison P. ; Barrett, Alexander S. ; Borgquist, Signe LU ; Ruffell, Brian ; Zakharevich, Igor ; Pham, Thanh T. ; Gruosso, Tina ; Kuasne, Hellen and Lakins, Johnathon N. , et al. (2020) In Nature Materials
Abstract

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... (More)

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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Contribution to journal
publication status
published
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in
Nature Materials
publisher
Nature Publishing Group
external identifiers
  • scopus:85096939740
  • pmid:33257795
ISSN
1476-1122
DOI
10.1038/s41563-020-00849-5
language
English
LU publication?
yes
id
969ad885-3f81-4335-adaa-4a20e0951403
date added to LUP
2020-12-14 13:10:14
date last changed
2024-04-17 21:45:26
@article{969ad885-3f81-4335-adaa-4a20e0951403,
  abstract     = {{<p>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.</p>}},
  author       = {{Maller, Ori and Drain, Allison P. and Barrett, Alexander S. and Borgquist, Signe and Ruffell, Brian and Zakharevich, Igor and Pham, Thanh T. and Gruosso, Tina and Kuasne, Hellen and Lakins, Johnathon N. and Acerbi, Irene and Barnes, J. Matthew and Nemkov, Travis and Chauhan, Aastha and Gruenberg, Jessica and Nasir, Aqsa and Bjarnadottir, Olof and Werb, Zena and Kabos, Peter and Chen, Yunn Yi and Hwang, E. Shelley and Park, Morag and Coussens, Lisa M. and Nelson, Andrew C. and Hansen, Kirk C. and Weaver, Valerie M.}},
  issn         = {{1476-1122}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Materials}},
  title        = {{Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression}},
  url          = {{http://dx.doi.org/10.1038/s41563-020-00849-5}},
  doi          = {{10.1038/s41563-020-00849-5}},
  year         = {{2020}},
}