Spine Oncology - Primary Spine Tumors.

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Abstract

[Indexed for MEDLINE] 19. J Exp Clin Cancer Res. 2025 Aug 4;44(1):225. doi: 10.1186/s13046-025-03478-5. Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1. Weich A(#)(1)(2)(3), Berges J(#)(4), Flamann C(4), Bitterer K(4), Singh KP(5), Chambers D(6), Lischer C(4), Lai X(1)(7), Wolkenhauer O(5)(8), Berking C(1)(2)(3), Krönke G(6)(9), Gupta S(5), Bruns H(#)(10)(11), Vera J(#)(12)(13)(14)(15), Macrophages RG(16). Author information: (1)Department of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, 91054, Erlangen, Germany. (2)Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany. (3)Deutsches Zentrum Immuntherapie (DZI), 91054, Erlangen, Germany. (4)Department of Internal Medicine 5, Hematology and Oncology, Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, 91054, Erlangen, Germany. (5)Department of Systems Biology and Bioinformatics, Universtität Rostock, Rostock, Germany. (6)Department of Internal Medicine 3, Uniklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054, Rheumatology, Erlangen, Germany. (7)Biomedicine Unit, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. (8)Leibniz-Institute for Food Systems Biology, Technical University of Munich, Freising, Germany. (9)Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany. (10)Department of Internal Medicine 5, Hematology and Oncology, Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, 91054, Erlangen, Germany. heiko.bruns@uk-erlangen.de. (11)Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054, Erlangen, Germany. heiko.bruns@uk-erlangen.de. (12)Department of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, 91054, Erlangen, Germany. julio.vera-gonzalez@uk-erlangen.de. (13)Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany. julio.vera-gonzalez@uk-erlangen.de. (14)Deutsches Zentrum Immuntherapie (DZI), 91054, Erlangen, Germany. julio.vera-gonzalez@uk-erlangen.de. (15)Laboratory of Systems Tumor Immunology, Department Dermatology, Friedrich-Alexander Universität Erlangen- Nürnberg, Hartmannstr. 14, 91052, Erlangen, Germany. julio.vera-gonzalez@uk-erlangen.de. (16)Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054, Erlangen, Germany. (#)Contributed equally BACKGROUND: The metastatic microenvironment is often rich in tumor-associated macrophages (TAMs). In uveal melanoma (UM), high levels of TAMs positively correlate with tumor progression and poorer prognosis. We hypothesize that the immunomodulation of TAMs can remodel the UM tumor microenvironment and make it more susceptible to therapeutic interventions. METHODS: In our work, we designed a novel computational pipeline that combines single-cell transcriptomics data, network analysis, multicriteria decision techniques, and pharmacophore-based docking simulations to select molecular targets and matching repurposable drugs for TAM immunomodulation. The method generates a ranking of drug-target interactions, the most promising of which are channeled towards experimental validation. RESULTS: To identify potential immunomodulatory targets, we created a network-based representation of the TAM interactome and extracted a regulatory core conditioned on UM expression data. Further, we selected 13 genes from this core (NLRP3, HMOX1, CASP1, GSTP1, NAMPT, HSP90AA1, B2M, ISG15, LTA4H, PTGS2, CXCL2, PLAUR, ZFP36, TANK) for pharmacophore-based virtual screening of FDA-approved compounds, followed by flexible molecular docking. Based on the ranked docking results, we chose the interaction between caspase-1 and clindamycin for experimental validation. Functional studies on macrophages confirmed that clindamycin inhibits caspase-1 activity and thereby inflammasome activation, leading to a decrease in IL-1β, IL-18, and gasdermin D cleavage products as well as a reduction in pyroptotic cell death. This clindamycin-mediated inhibition of caspase-1 was also observable in TAMs derived from the bone marrow of multiple myeloma patients. CONCLUSIONS: Our computational workflow for drug repurposing identified clindamycin as an efficacious inhibitor of caspase-1 that suppresses inflammasome activity and pyroptosis in vitro in TAMs. [Image: see text] © 2025. The Author(s). DOI: 10.1186/s13046-025-03478-5 PMCID: PMC12320367