Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression.
Journal
Nature materials
ISSN: 1476-4660
Titre abrégé: Nat Mater
Pays: England
ID NLM: 101155473
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
08
12
2017
accepted:
30
09
2020
pubmed:
2
12
2020
medline:
14
5
2021
entrez:
1
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33257795
doi: 10.1038/s41563-020-00849-5
pii: 10.1038/s41563-020-00849-5
pmc: PMC8005404
mid: NIHMS1633903
doi:
Substances chimiques
Collagen
9007-34-5
Protein-Lysine 6-Oxidase
EC 1.4.3.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
548-559Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL007171
Pays : United States
Organisme : NIH HHS
ID : S10 OD021641
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222508
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR001081
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA174929
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192914
Pays : United States
Organisme : NCI NIH HHS
ID : R33 CA183685
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA242447
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227942
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA108462
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA057621
Pays : United States
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