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While there has been significant work in the development of additional models, few have been created without oncogenic transformation. We derived a primary prostate cancer cell line from a patient with localized Gleason 7 prostate cancer\u2014designated CaB34\u2014which spontaneously immortalized. We leveraged CaB34 to generate a paired radioresistant subline, CaB34-CF, using a clinically relevant fractionated radiotherapy schedule. These two paired cell lines were investigated extensively to determine their molecular characteristics and therapy responses. Both CaB34 and CaB34-CF express prostate-specific markers, including KRT18, NKX3.1, and AMACR. Multi-omic analyses using RNAseq and shotgun proteomics identified NNMT as the most significantly dysregulated component in CaB34-CF. A bioinformatic analysis determined that NNMT was more abundant within prostate tumors compared to benign prostate, suggesting a role in tumor progression. Knockdown studies of NNMT demonstrated significant radiosensitization of CaB34-CF cells, which was largely a result of increased radiation-induced cellular senescence. Growth as 3D organoids was significantly higher in the CaB34-CF line, and demonstrated a less structured pattern of expression of cytokeratin markers. Radiosensitization with NNMT siRNA was recapitulated in a 3D organoid clonogenic assay in CaB34-CF cells. Our research provides a paired primary model of treatment-na\u00efve and radioresistant disease to address mechanisms of therapy resistance, while expanding the repertoire of localized prostate cancer cell lines for the research community. In addition, our findings present NNMT as a potential therapeutic target for sensitization of radioresistant disease.<\/jats:p>","DOI":"10.3390\/cells14110819","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T12:27:09Z","timestamp":1748867229000},"page":"819","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel Primary Cell Line Model of Localized Prostate Cancer and Radioresistance\u2014A Role for Nicotinamide N-Methyltransferase"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5413-4739","authenticated-orcid":false,"given":"Jessica A.","family":"Wright","sequence":"first","affiliation":[{"name":"Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada"},{"name":"Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2C4, 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