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

Autor: Johnathon N. Lakins, Thanh T. Pham, Ori Maller, Irene Acerbi, Andrew C. Nelson, Travis Nemkov, Hellen Kuasne, Allison P. Drain, Olöf Bjarnadottir, Igor Zakharevich, Morag Park, Brian Ruffell, J. Matthew Barnes, Kirk C. Hansen, Aastha Chauhan, E. Shelley Hwang, Valerie M. Weaver, Lisa M. Coussens, Aqsa Nasir, Alexander S. Barrett, Signe Borgquist, Jessica Gruenberg, Tina Gruosso, Peter Kabos, Zena Werb, Yunn Yi Chen
Rok vydání: 2020
Předmět:
Breast Neoplasms/immunology
Biopsy
02 engineering and technology
01 natural sciences
Metastasis
Protein-Lysine 6-Oxidase
chemistry.chemical_compound
Tumor-Associated Macrophages
2.1 Biological and endogenous factors
General Materials Science
Cancer
Tumor
biology
Chemistry
Tumor-Associated Macrophages/metabolism
Middle Aged
021001 nanoscience & nanotechnology
Condensed Matter Physics
Protein-Lysine 6-Oxidase/metabolism
Mechanics of Materials
cardiovascular system
Immunohistochemistry
Female
Collagen
0210 nano-technology
Adult
Stromal cell
Lysyl hydroxylase
Stromal Cells/metabolism
Breast Neoplasms
Lysyl oxidase
macromolecular substances
010402 general chemistry
Article
Cell Line
Stroma
Cell Line
Tumor
Collagen/metabolism
Breast Cancer
medicine
Humans
Nanoscience & Nanotechnology
Mechanical Engineering
technology
industry
and agriculture
General Chemistry
medicine.disease
0104 chemical sciences
Hydroxylysine
biology.protein
Cancer research
Stromal Cells
Zdroj: Nature materials, vol 20, iss 4
Maller, O, Drain, A P, Barrett, A S, Borgquist, S, Ruffell, B, Zakharevich, I, Pham, T T, Gruosso, T, Kuasne, H, Lakins, J N, Acerbi, I, Barnes, J M, Nemkov, T, Chauhan, A, Gruenberg, J, Nasir, A, Bjarnadottir, O, Werb, Z, Kabos, P, Chen, Y-Y, Hwang, E S, Park, M, Coussens, L M, Nelson, A C, Hansen, K C & Weaver, V M 2021, ' Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression ', Nature Materials, vol. 20, no. 4, pp. 548-559 . https://doi.org/10.1038/s41563-020-00849-5
Nature materials
ISSN: 1476-4660
1476-1122
DOI: 10.1038/s41563-020-00849-5
Popis: 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.
Databáze: OpenAIRE
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