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Inflammation 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. Synopsis: The molecular origins of chronic tissue inflammation and its impact on cancer growth remain elusive. This study identifies TRPM8 transcripts as androgen-independent driver of sterile inflammation in the prostate gland, promoting anticancer innate immunity in the tumor microenvironment. TRPM8 RNA is secreted via extracellular vesicles (EVs) by normal and prostate cancer cells in the absence of cell damage. Upon EV endocytosis, TRPM8 mRNA binds TLR3 in endosomes, thereby promoting NF-kB/IRF3 activation and release of pro-inflammatory signals. NF-kB induces the androgen-independent expression of PSA encoded by the KLK3 gene. TRPM8/TLR3 signaling induces inflammation in prostate cancer xenografts, promoting infiltration and anticancer activity of NK cells. TLR3-activation by extracellular vesicle-delivered TRPM8 mRNA triggers aseptic inflammation in the prostate epithelium, promoting tumor suppression by NK cells. [ABSTRACT FROM AUTHOR]

The "QuantitatEVs: multiscale analyses, from bulk to single vesicle" workshop aimed to discuss quantitative strategies and harmonized wet and computational approaches toward the comprehensive analysis of extracellular vesicles (EVs) from bulk to single vesicle analyses with a special focus on emerging technologies. The workshop covered the key issues in the quantitative analysis of different EV‐associated molecular components and EV biophysical features, which are considered the core of EV‐associated biomarker discovery and validation for their clinical translation. The in‐person‐only workshop was held in Trento, Italy, from January 31st to February 2nd, 2023, and continued in Milan on February 3rd with "Next Generation EVs," a satellite event dedicated to early career researchers (ECR). This report summarizes the main topics and outcomes of the workshop. [ABSTRACT FROM AUTHOR]

Multi‐analyte liquid biopsies represent an emerging opportunity for non‐invasive cancer assessment. We developed ONCE (One Aliquot for Circulating Elements), an approach for the isolation of extracellular vesicles (EV) and cell‐free DNA (cfDNA) from a single aliquot of blood. We assessed ONCE performance to classify HER2‐positive early‐stage breast cancer (BrCa) patients by combining EV‐associated RNA (EV‐RNA) and cfDNA signals on n = 64 healthy donors (HD) and non–metastatic BrCa patients. Specifically, we isolated EV‐enriched samples by a charge‐based (CB) method and investigated EV‐RNA and cfDNA by next‐generation sequencing (NGS) and by digital droplet PCR (ddPCR). Sequencing of cfDNA and EV‐RNA from HER2‐ and HER2+ patients demonstrated concordance with in situ molecular analyses of matched tissues. Combined analysis of the two circulating analytes by ddPCR showed increased sensitivity in ERBB2/HER2 detection compared to single nucleic acid components. Multi‐analyte liquid biopsy prediction performance was comparable to tissue‐based sequencing results from TCGA. Also, imaging flow cytometry analysis revealed HER2 protein on the surface of EV isolated from the HER2+ BrCa plasma, thus corroborating the potential relevance of studying EV as companion analyte to cfDNA. This data confirms the relevance of combining cfDNA and EV‐RNA for HER2 cancer assessment and supports ONCE as a valuable tool for multi‐analytes liquid biopsies' clinical implementation. [ABSTRACT FROM AUTHOR]