uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils

Autor: Bernd Uhl, Laura AMittmann, Julian Dominik, Roman Hennel, Bojan Smiljanov, Florian Haring, Johanna BSchaubächer, Constanze Braun, Lena Padovan, Robert Pick, Martin Canis, Christian Schulz, Matthias Mack, Ewgenija Gutjahr, Peter Sinn, Jörg Heil, Katja Steiger, Sandip M Kanse, Wilko Weichert, Markus Sperandio, Kirsten Lauber, Fritz Krombach, Christoph A Reichel
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 13, Iss 6, Pp n/a-n/a (2021)
Druh dokumentu: article
ISSN: 1757-4684
1757-4676
20201311
DOI: 10.15252/emmm.202013110
Popis: Abstract 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‐1high tumors.
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