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resistance remains universal for patients with metastatic prostate cancer, driven by androgen receptor alterations and lineage state transitions. Identifying the evolution of lineage transitions in treatment resistance has been limited by the challenges of collecting serial tissue biopsies on treatment, which can be overcome using blood-based liquid biopsies. Using a novel circulating tumor cell (CTC) isolation approach, we collected 273 CTC samples from 117 patients with metastatic prostate cancer for RNA sequencing. One hundred forty-six samples from 70 patients had tumor purity comparable with tissue biopsies. We identified four CTC transcriptional phenotypes, mirroring lineage states identified in the tissue. Patients with a luminal-B\u2013like CTC phenotype defined by persistent androgen receptor signaling and high proliferation, as well as those with a neuroendocrine CTC phenotype, had significantly shorter survival than patients with luminal-A\u2013like and low proliferation phenotypes. In a prospective substudy, pretreatment CTC luminal-B\u2013like phenotype was associated with early progression on 177Lu\u2013PSMA-617.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Treatment resistance remains a universal driver of lethal metastatic prostate cancer, associated with acquired genomic alterations and lineage transitions. Using a novel high-purity CTC isolation approach for CTC transcriptional profiling, we identified four lineage phenotypes differentially associated with prognosis in metastatic prostate cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1509","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T11:10:36Z","timestamp":1738840236000},"page":"969-987","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["High-Purity CTC RNA Sequencing Identifies Prostate Cancer Lineage Phenotypes Prognostic for Clinical Outcomes"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0128-3033","authenticated-orcid":false,"given":"Marina N.","family":"Sharifi","sequence":"first","affiliation":[{"name":"1Carbone Cancer Center, University of Wisconsin\u2013Madison, Madison, Wisconsin."},{"name":"2Department of Medicine, University of 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