uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils
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 heter...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202013110 |
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| author | Bernd Uhl Laura A Mittmann Julian Dominik Roman Hennel Bojan Smiljanov Florian Haring Johanna B Schaubächer 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 |
| author_facet | Bernd Uhl Laura A Mittmann Julian Dominik Roman Hennel Bojan Smiljanov Florian Haring Johanna B Schaubächer 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 |
| author_sort | Bernd Uhl |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4c70973c2a744ff8b94cdcdb9b282bf8 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-4c70973c2a744ff8b94cdcdb9b282bf82025-08-20T03:46:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-05-0113611610.15252/emmm.202013110uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophilsBernd Uhl0Laura A Mittmann1Julian Dominik2Roman Hennel3Bojan Smiljanov4Florian Haring5Johanna B Schaubächer6Constanze Braun7Lena Padovan8Robert Pick9Martin Canis10Christian Schulz11Matthias Mack12Ewgenija Gutjahr13Peter Sinn14Jörg Heil15Katja Steiger16Sandip M Kanse17Wilko Weichert18Markus Sperandio19Kirsten Lauber20Fritz Krombach21Christoph A Reichel22Department of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Radiation Oncology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenWalter Brendel Centre of Experimental Medicine, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Cardiology, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Internal Medicine, University of RegensburgInstitute for Pathology, University of HeidelbergInstitute for Pathology, University of HeidelbergDepartment of Gynecology and Obstetrics, University of HeidelbergDepartment of Pathology, Technical University of MunichInstitute of Basic Medical Sciences, University of OsloDepartment of Pathology, Technical University of MunichInstitute of Cardiovascular Physiology and Pathophysiology, Ludwig‐Maximilians‐Universität MünchenDepartment of Radiation Oncology, University Hospital, Ludwig‐Maximilians‐Universität MünchenWalter Brendel Centre of Experimental Medicine, University Hospital, Ludwig‐Maximilians‐Universität MünchenDepartment of Otorhinolaryngology, University Hospital, Ludwig‐Maximilians‐Universität MünchenAbstract 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.https://doi.org/10.15252/emmm.202013110biomarkerbreast cancerfibrinolysisinnate immunityneutrophils |
| spellingShingle | Bernd Uhl Laura A Mittmann Julian Dominik Roman Hennel Bojan Smiljanov Florian Haring Johanna B Schaubächer 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 uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils EMBO Molecular Medicine biomarker breast cancer fibrinolysis innate immunity neutrophils |
| title | uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils |
| title_full | uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils |
| title_fullStr | uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils |
| title_full_unstemmed | uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils |
| title_short | uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils |
| title_sort | upa pai 1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils |
| topic | biomarker breast cancer fibrinolysis innate immunity neutrophils |
| url | https://doi.org/10.15252/emmm.202013110 |
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