Abstract
Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.
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Data availability
The data analyzed during this study are included in this article and the supplemental data files. Additional supporting data are available from the corresponding authors upon reasonable request.
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Acknowledgements
The authors thank C. Bosi, F. Poletti, A.C. Sarti, and S. Falzoni for their contribution to this study. PP is grateful to C. degli Scrovegni for her continuous support.
Funding
The Signal Transduction Laboratory is supported by the Italian Association for Cancer Research (IG-23670 to PP, IG-19803 to CG and IG 22883 to FDV), A-ROSE, Progetti di Rilevante Interesse Nazionale (PRIN2017E5L5P3 to PP and PRIN20177E9EPY to CG), the Italian Ministry of Health (GR-2019-12369646 to SM), the European Research Council (853057-InflaPML to CG) and local funds from the University of Ferrara to CG and PP. MRW was supported by the National Science Centre, Poland (UMO-2018/29/B/NZ1/00589). MLA was funded by a Polish National Science Centre grant (UMO-2015/17/D/NZ1/00030). MP is supported by an AIRC research fellowship (ID: 26665).
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CG conceived the study. SM performed most of the experiments and prepared the figures. MP and SMa performed the proximity ligation assay studies. MP generated the CRISPR knockout clones. CG directed and coordinated the study, oversaw all the experiments, and wrote the manuscript. PP supervised the study and oversaw the experiments. F.D.V. collaborated in experiments related to P2X7R. GM, MRW, and MLA performed the co-immunoprecipitation experiments. RG, GL and LA performed the immunohistochemical analysis. LA helped in writing the manuscript. SM and MP provided advice for the in vivo experiments. FN performed the flow cytometry experiments. MB and KI performed the bone marrow replacement experiment. CB and BV helped with some experiments. SM performed the Western blot, ELISA, and subcellular fractionation studies. FK performed the SPR studies. FF, AB, and RG helped in the patient’s cohorts selection. All authors read and approved the final manuscript.
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Procedures involving animals and their care were in conformity with institutional guidelines, and the Animal Ethics Committee approved all experimental protocols (authorization nos. 481/2017-PR and CBCC2.N.BH4 approved by the Italian Ministry of Health). The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the University Hospital of Ferrara (CE-AVEC: 1016/2020/Oss/UniFe).
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Missiroli, S., Perrone, M., Gafà, R. et al. PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment. Cell Death Differ 30, 429–441 (2023). https://doi.org/10.1038/s41418-022-01095-9
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DOI: https://doi.org/10.1038/s41418-022-01095-9
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