Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer
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Published:2024-02-05
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ISSN:1460-2075
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Container-title:The EMBO Journal
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language:en
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Short-container-title:EMBO J
Author:
Alaimo AlessandroORCID, Genovesi SachaORCID, Annesi Nicole, De Felice DarioORCID, Subedi Saurav, Macchia Alice, La Manna Federico, Ciani Yari, Vannuccini FedericoORCID, Mugoni Vera, Notarangelo MichelaORCID, Libergoli MichelaORCID, Broso FrancescaORCID, Taulli Riccardo, Ala UgoORCID, Savino Aurora, Cortese MartinaORCID, Mirzaaghaei SomayehORCID, Poli ValeriaORCID, Bonapace Ian Marc, Papotti Mauro Giulio, Molinaro Luca, Doglioni Claudio, Caffo Orazio, Anesi Adriano, Nagler Michael, Bertalot GiovanniORCID, Carbone Francesco Giuseppe, Barbareschi MattiaORCID, Basso Umberto, Dassi Erik, Pizzato Massimo, Romanel AlessandroORCID, Demichelis Francesca, Kruithof-de Julio Marianna, Lunardi AndreaORCID
Abstract
AbstractInflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.
Funder
Giovanni Armenise-Harvard Foundation Ministero dell'Istruzione, dell'Università e della Ricerca Fondazione AIRC per la ricerca sul cancro ETS Lega Italiana Lotta ai Tumori Cancer Research UK Krebsliga Schweiz Swiss National Science Foundation Fondazione Umberto Veronesi University of Trento
Publisher
Springer Science and Business Media LLC
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience
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