biostudies-literatureSharifi MNUniversity of Wisconsin Office of the Vice Chancellor for Research and Graduate EducationNCI NIH HHSProstate Cancer FoundationNational Institutes of HealthDepartment of Defense969-987https://www.ebi.ac.uk/biostudies/studies/S-EPMC12046329biostudies-literatureUnknown15(5)The development of treatment resistance remains universal for patients with metastatic prostate cancer, driven by AR 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. Utilizing a novel circulating tumor cell (CTC) isolation approach, we collected 273 CTC samples from 117 patients with metastatic prostate cancer for RNA sequencing. 146 samples from 70 patients had tumor purity comparable to tissue biopsies. We identified four CTC transcriptional phenotypes, mirroring lineage states identified in tissue. Patients with a luminal-B-like CTC phenotype defined by persistent AR signaling andCancer discoveryHigh-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes.PMC12046329R01CA276269P30 CA008748R01 CA266452R50CA293840PC180469P30 CA014520PC230533P50CA269011P50 CA2690112024 TACTICAL AwardR01CA280056R01 CA247479R50 CA293840UH2 CA260389P50CA097186Movember Foundation—PCF Challenge AwardP50 CA0971861UH2CA260389R01 CA234715R01 CA280056R01 CA276269R01CA234715-01R50 CA283815PC190039R50CA283815PC220240R01CA266452PC2003342022 Point Biopharma Young VAlor Investigator AwardPICIDP2 OD0307342023 Debbie & Mark Attanasio – PCF Young Investigator Award2021 Michael and Patricia Berns-PCF Young Investigator AwardR01CA247479Krause HMMora-Rodriguez LYu MSjostrom MEmamekhoo HChang AHLang JMFloberg JMZhao SGWells MBootsma MLFeng FYKosoff DCarreno VTaylor AKSharifi MNTagawa STSchehr JLHelzer KTNelson PSSperger JMChoudhury ADBlitzer GCReese SRRathkopf DEKaufmann KRHeath EIWei XXKyriakopoulos CENunamaker LALinebarger CTippins KEDehm SMArmstrong AJBeltran HMcKay RRfalseHigh-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes.The development of treatment resistance remains universal for patients with metastatic prostate cancer, driven by AR 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. Utilizing a novel circulating tumor cell (CTC) isolation approach, we collected 273 CTC samples from 117 patients with metastatic prostate cancer for RNA sequencing. 146 samples from 70 patients had tumor purity comparable to tissue biopsies. We identified four CTC transcriptional phenotypes, mirroring lineage states identified in tissue. Patients with a luminal-B-like CTC phenotype defined by persistent AR signaling and2025-01-01T00:00:00Z2025 May2026-06-02T20:56:17.352Z2025-07-06T03:05:51.715ZS-EPMC120463293991291210.1158/2159-8290.CD-24-1509