ArticleCellular oncology (Dordrecht, Netherlands)2020
Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation.
Article in Cellular oncology (Dordrecht, Netherlands), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 64 citations in OpenAlex.
- A protein-small molecule conjugate as a bispecific inhibitor of proteases implicated in cancer metastasis.Scientific reports · 2026Article
- Responses of Nasal Polyp-Derived Macrophages to Inflammatory Cues and Potential Pathological Roles in Type 2 Chronic Rhinosinusitis With Nasal Polyps.Clinical and experimental otorhinolaryngology · 2026Article
- Acinar-ductal metaplasia in pancreatitis and pancreatic ductal adenocarcinoma.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- F2R and MXRA5: the metabolic obesity-derived biomarkers for immunosuppression and poor survival in triple-negative breast cancer.Discover oncology · 2026Article
- Novel Biomarkers for Lymph Node Metastasis and Prognosis of Bladder Cancer by Bioinformatics Analysis.ACS omega · 2025Article
- Disulfidptosis classification of pancreatic carcinoma reveals correlation with clinical prognosis and immune profile.Hereditas · 2025Article
- Domestication and feedback: bidirectional hijacking in pancreatic ductal adenocarcinoma microenvironment.Frontiers in immunology · 2025Review
- Endogenous SLPI contributes to the regulation of inflammatory responses in peritoneal macrophages by modulating MMP-9 production.Frontiers in immunology · 2025Article
- High levels of fibrotic tumor components are associated with recurrence and intratumoral immune status in advanced colorectal cancer patients.Scientific reports · 2024Article
- Recombinant hirudin and PAR-1 regulate macrophage polarisation status in diffuse large B-cell lymphoma.BMC biotechnology · 2024Article
- Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment.Cell & bioscience · 2024Review
- Single-nuclei transcriptome analysis of channel catfish spleen provides insight into the immunome of an aquaculture-relevant species.PloS one · 2024Article
- Differential Effects of Pancreatic Cancer-Derived Extracellular Vesicles Driving a Suppressive Environment.International journal of molecular sciences · 2023Article
- Comparative analysis of single-cell transcriptome reveals heterogeneity in the tumor microenvironment of lung adenocarcinoma and brain metastases.Discover oncology · 2023Article
- Integration of Single-Cell RNA Sequencing and Bulk RNA Sequencing Reveals That TAM2-Driven Genes Affect Immunotherapeutic Response and Prognosis in Pancreatic Cancer.International journal of molecular sciences · 2023Article
- Downregulation of DNA methylation enhances differentiation of THP-1 cells and induces M1 polarization of differentiated macrophages.Scientific reports · 2023Article
- Polarization of Cancer-Associated Macrophages Maneuver Neoplastic Attributes of Pancreatic Ductal Adenocarcinoma.Cancers · 2023Review
- The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights.Cancers · 2023Review
- PP2Ac/STRN4 negatively regulates STING-type I IFN signaling in tumor-associated macrophages.The Journal of clinical investigation · 2023Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
purposeTargeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the functional interplay between PAR1, macrophages and tumor cells remains unexplored. Here we address the PAR1-macrophage-tumor cell crosstalk and assess its contributions to tumor progression.
methodsPAR1 expression and macrophage infiltration were correlated in primary PDAC biopsies using gene expression datasets and tissue microarrays. Medium transfer experiments were used to evaluate the functional consequences of macrophage-tumor cell crosstalk and to assess the contribution of PAR1 to the observed responses. PAR1 cleavage assays were used to identify a macrophage-secreted PAR1 agonist, and the effects of candidate proteases were assessed in medium transfer experiments with specific inhibitors and/or recombinant agonist.
resultsPAR1 expression correlates with macrophage infiltration in primary PDACs, and macrophages induce mesenchymal transition of PDAC cells through PAR1 activation. Protease profiling identified macrophage-secreted matrix metalloprotease 9 (MMP9) as the relevant PAR1 agonist in PDAC. PAR1 and/or MMP9 inhibition limited macrophage-driven mesenchymal transition. Likewise, preventing mesenchymal transition by silencing ZEB1 or by pharmacological inhibition of the MMP9/PAR1 axis significantly reduced the ability of tumor cells to survive the anti-tumor activities of macrophages.
conclusionMacrophages secrete MMP9, which acts upon PDAC cell PAR1 to induce mesenchymal transition. This macrophage-induced mesenchymal transition supports the tumor-promoting role of macrophage influx, explaining the dichotomous contributions of these immune cells to tumor growth.
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