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

Uhl, Bernd; Mittmann, L; Dominik, Julian; Hennel, Roman; Smiljanov, Bojan; Haring, Florian; Schaubächer, J; Braun, Cordula; Padovan, Lena; Pick, Robert; Canis, Martin; Schulz, Christian; Mack, Matthias; Gutjahr, Ewgenija; Sinn, Hans‐Peter; Heil, Jörg; Steiger, Katja; Kanse, Sandip M.; Weichert, Wilko; Sperandio, Markus; Lauber, Kirsten; Krombach, Fritz; Reichel, Christoph

doi:10.15252/emmm.202013110

Cited by 8 publications

(10 citation statements)

References 52 publications

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“…M1 and M2 macrophages are considered antitumor and protumor, respectively ( 34 ). Neutrophils have also been shown to have cancer-promoting effects ( 35 , 36 ). However, we did not observe any influence of myeloid leukocyte depletion on tumor growth in the CDX model (fig.…”

Section: Resultsmentioning

confidence: 99%

“…Myeloid leukocytes play important and complex roles in cancer development ( 34 , 36 ). A recent study showed that heteromerization of uPA and plasminogen activator inhibitor-1 (PAI-1), two key components of the uPA-uPAR system, promotes breast cancer progression by attracting tumorigenic neutrophils ( 35 ). In addition, M1 and M2 macrophages are considered to have antitumor and protumor function, respectively ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic strategies targeting uPAR potentiate anti–PD-1 efficacy in diffuse-type gastric cancer

et al. 2022

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The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti–Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line–derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor–expressing T cells based on the novel anti-uPAR effectively kill DGC patient–derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Therapeutic strategies targeting uPAR potentiate anti–PD-1 efficacy in diffuse-type gastric cancer

et al. 2022

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“…Importantly, pre-incubation with mAb-2E3 was able to block the binding between LRP1-Cluster II-Fc and PAI-1, with the IC50 value of mAb-2E3 was 26.45 nM (Fig. 7B), while the IC50 value of mIgG was 2.96e 25 nM.…”

Section: Mab-2e3 Blocks the Binding Between Lrp1-cluster Ii-fc And Pai-1mentioning

confidence: 95%

“…Vitronectin binds to PAI-1 through the helices hD, hE, and hF in the flexible joint region. LRP1 endocytoses PAI-1 or PAI-1-/uPA/tPA mainly through recognition with several key residues of helix hD, such as K60, K69, R76 and R138 25 , 26 . In response to this feature, small molecule inhibitors and antibodies targeting PAI-1 have been developed.…”

Section: Introductionmentioning

confidence: 99%

Anti-PAI-1 Monoclonal Antibody Inhibits the Metastasis and Growth of Esophageal Squamous Cell Carcinoma

Zheng¹,

Meng²,

Qu³

et al. 2023

J. Cancer

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Plasminogen activator inhibitor (PAI-1) is highly expressed in esophageal squamous cell carcinoma (ESCC) and strongly contributes to metastasis, making it a potential target for ESCC therapy. However, the antibodies and inhibitors targeting PAI-1 have not shown good therapeutic effect in the in vivo experiments yet. Here, we generated a panel of novel monoclonal antibodies (mAbs) against PAI-1. Analysis of PAI-1 expression in 90 tissue specimens and 128 serum specimens from ESCC patients with these mAbs confirmed that PAI-1 levels was significantly correlated with metastasis and poor survival. In addition, we found that high PAI-1 expression contributed to the enhanced motility and invasiveness of two ESCC cell lines. Next, mAb-1E2 and mAb-2E3, which have highest affinity with PAI-1, were shown to possess strong inhibitory effects on ESCC migration and invasion. Anti-tumor and anti-metastatic effects of mAb-2E3 were further demonstrated in the experimental animal models. Finally, LRP1 was identified as key factor mediating the pro-invasive function of PAI-1 and the anti-invasive capacity of mAb-2E3 in ESCC cells. The mAb-2E3 markedly decreased STAT1 phosphorylation levels and blocked the binding between PAI-1 and LRP1-ClusterII domain. Collectively, mAb-2E3 developed by our lab may be an effective antibody drug which can be used for anti-metastatic therapy in ESCC.

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“…Blockade of uPA‐PAI‐1 heteromerization by a novel small molecule inhibitor WX‐340 effectively prevents tumor progression. [ 148 ] Wang et al demonstrate that SPI1 (Salmonella pathogenicity island 1) physically interacts with SPIB to promote aerobic glycolysis in colon cancer cells, which induces pro‐tumor polarization of neutrophils and in turn their delivery of SPI1 mRNA into cancer cells, constituting a positive feedback loop to favor cancer progression. [ 149 ] Therapeutic targeting of SPIB‐SPI1 interaction with an inhibitory peptide of 11 amino acids (termed as SIP‐11) inhibits aerobic glycolysis and cancer progression.…”

Section: Targeting Neutrophils For Cancer Therapymentioning

confidence: 99%

Engineering and Targeting Neutrophils for Cancer Therapy

Zhang,

Gu,

Wang

et al. 2024

Advanced Materials

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Neutrophils are the most abundant white blood cells in the circulation and act as the first line of defense against infections. Increasing evidence suggests that neutrophils possess heterogeneous phenotypes and functional plasticity in human health and diseases, including cancer. Neutrophils play multifaceted roles in cancer development and progression, and an N1/N2 paradigm of neutrophils in cancer has been proposed, where N1 neutrophils exert anti‐tumor properties while N2 neutrophils display tumor‐supportive and immune‐suppressive functions. Selective activation of beneficial neutrophil population and targeted inhibition or re‐polarization of tumor‐promoting neutrophils has shown an important potential in tumor therapy. In addition, due to the natural inflammation‐responsive and physical barrier‐crossing abilities, neutrophils and their derivatives (membranes and extracellular vesicles) are regarded as advanced drug delivery carriers for enhanced tumor targeting and improved therapeutic efficacy. In this review, we comprehensively presented the recent advances in engineering neutrophils for drug delivery and targeting neutrophils for remodeling tumor microenvironment. This review will provide a broad understanding of the potential of neutrophils in cancer therapy.This article is protected by copyright. All rights reserved

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

Cited by 8 publications

References 52 publications

Therapeutic strategies targeting uPAR potentiate anti–PD-1 efficacy in diffuse-type gastric cancer

Therapeutic strategies targeting uPAR potentiate anti–PD-1 efficacy in diffuse-type gastric cancer

Anti-PAI-1 Monoclonal Antibody Inhibits the Metastasis and Growth of Esophageal Squamous Cell Carcinoma

Engineering and Targeting Neutrophils for Cancer Therapy

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