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

Uhl, Bernd; Mittmann, Laura; Dominik, Julian; Hennel, Roman; Smiljanov, Bojan; Haring, Florian; Schaubaecher, Johanna; Braun, Constanze; Padovan, Lena; Pick, Robert; Canis, Martin; Schulz, Christian; Mack, Matthias; Gutjahr, Ewgenija; Sinn, Peter; Heil, Joerg; Steiger, Katja; Kanse, Sandip M.; Weichert, Wilko; Sperandio, Markus; Lauber, Kirsten; Krombach, Fritz und Reichel, Christoph A. (2021): uPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils. In: EMBO Molecular Medicine, Bd. 13, Nr. 6, e13110

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-1(high) tumors.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1757-4676
• Sprache: Englisch