Open AccessuPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils
Author(s) -
Uhl Bernd,
Mittmann Laura,
Dominik Julian,
Hennel Roman,
Smiljanov Bojan,
Haring Florian,
Schaubächer Johanna,
Braun Constanze,
Padovan Lena,
Pick Robert,
Canis Martin,
Schulz Christian,
Mack Matthias,
Gutjahr Ewgenija,
Sinn Peter,
Heil Jörg,
Steiger Katja,
Kanse Sandip M,
Weichert Wilko,
Sperandio Markus,
Lauber Kirsten,
Krombach Fritz,
Reichel Christoph A
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013110
Subject(s) - cancer research , plasminogen activator , urokinase receptor , tumor progression , cancer , immune system , biology , plasminogen activator inhibitor 1 , metastasis , immunology , blockade , breast cancer , tumor microenvironment , receptor , endocrinology , biochemistry , genetics
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.