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In this study, we performed single-cell transcriptomic profiling of diagnostic prostate biopsy specimens from five patients with treatment-na\u00efve mHNPC using Fixed RNA Profiling. Integrated and case-specific analyses characterized epithelial heterogeneity and lineage-associated transcriptional programs. Across 17,825 high-quality single cells, epithelial heterogeneity was identified in all cases. In addition to luminal androgen receptor (AR)-dependent epithelial cells, reproducible basal-associated epithelial populations with reduced AR signaling and stem-like transcriptional features were observed across tumors. Epithelial\u2013mesenchymal transition (EMT)-related transcriptional programs were detected across multiple epithelial states with inter-case variability without forming a distinct EMT cluster, whereas no transcriptionally discrete neuroendocrine epithelial cluster was identified at baseline. These findings demonstrate that treatment-na\u00efve mHNPC harbors pre-existing basal-associated epithelial states that contribute to intrinsic tumor heterogeneity at diagnosis. The presence of AR-low and stem-like epithelial populations prior to systemic therapy suggests a potential role for lineage plasticity in the aggressive biological behavior of metastatic prostate cancer.<\/jats:p>","DOI":"10.3390\/ijms27125405","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:46:28Z","timestamp":1781588788000},"page":"5405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-Cell Analysis Reveals Pre-Existing Basal-Associated Epithelial States in Metastatic Hormone-Na\u00efve Prostate Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6656-4261","authenticated-orcid":false,"given":"Ryuta","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Urology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mami","family":"Chosei","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon 791-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7724-2225","authenticated-orcid":false,"given":"Tomohisa","family":"Sakaue","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon 791-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2229-0948","authenticated-orcid":false,"given":"Noriyoshi","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Urology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8992-4167","authenticated-orcid":false,"given":"Tadahiko","family":"Kikugawa","sequence":"additional","affiliation":[{"name":"Department of Urology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Saika","sequence":"additional","affiliation":[{"name":"Department of Urology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1056\/NEJMoa1702900","article-title":"Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy","volume":"377","author":"James","year":"2017","journal-title":"N. 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