uPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils.
biomarker
breast cancer
fibrinolysis
innate immunity
neutrophils
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 06 2021
07 06 2021
Historique:
revised:
28
04
2021
received:
14
07
2020
accepted:
25
03
2021
pubmed:
18
5
2021
medline:
26
10
2021
entrez:
17
5
2021
Statut:
ppublish
Résumé
High intratumoral levels of urokinase-type plasminogen activator (uPA)-plasminogen activator inhibitor-1 (PAI-1) heteromers predict impaired survival and treatment response in early breast cancer. The pathogenetic role of this protein complex remains obscure. Here, we demonstrate that heteromerization of uPA and PAI-1 multiplies the potential of the single proteins to attract pro-tumorigenic neutrophils. To this end, tumor-released uPA-PAI-1 utilizes very low-density lipoprotein receptor and mitogen-activated protein kinases to initiate a pro-inflammatory program in perivascular macrophages. This enforces neutrophil trafficking to cancerous lesions and skews these immune cells toward a pro-tumorigenic phenotype, thus supporting tumor growth and metastasis. Blockade of uPA-PAI-1 heteromerization by a novel small-molecule inhibitor interfered with these events and effectively prevented tumor progression. Our findings identify a therapeutically targetable, hitherto unknown interplay between hemostasis and innate immunity that drives breast cancer progression. As a personalized immunotherapeutic strategy, blockade of uPA-PAI-1 heteromerization might be particularly beneficial for patients with highly aggressive uPA-PAI-1
Identifiants
pubmed: 33998175
doi: 10.15252/emmm.202013110
pmc: PMC8185543
doi:
Substances chimiques
Plasminogen Activator Inhibitor 1
0
Urokinase-Type Plasminogen Activator
EC 3.4.21.73
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13110Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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