High-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes Journal Article
| Authors: | Sharifi, M. N.; Sperger, J. M.; Taylor, A. K.; Tippins, K. E.; Reese, S. R.; Carreno, V.; Kaufmann, K. R.; Chang, A. H.; Nunamaker, L. A.; Linebarger, C.; Mora-Rodriguez, L.; Schehr, J. L.; Krause, H. M.; Helzer, K. T.; Bootsma, M. L.; Blitzer, G. C.; Floberg, J. M.; Kyriakopoulos, C. E.; Emamekhoo, H.; Heath, E. I.; Wells, M.; Tagawa, S. T.; Sjöström, M.; Choudhury, A. D.; Yu, M.; Armstrong, A. J.; Rathkopf, D. E.; Beltran, H.; Nelson, P. S.; Feng, F. Y.; Dehm, S. M.; Kosoff, D.; Wei, X. X.; McKay, R. R.; Zhao, S. G.; Lang, J. M. |
| Article Title: | High-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes |
| Abstract: | The development of treatment 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–like 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–like and low proliferation phenotypes. In a prospective substudy, pretreatment CTC luminal-B–like phenotype was associated with early progression on177 Lu–PSMA-617. Significance: 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. © 2025 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | cancer survival; human tissue; protein expression; aged; major clinical study; overall survival; prospective study; polymerase chain reaction; cell proliferation; prostate specific antigen; quality control; phenotype; cd34 antigen; carcinoembryonic antigen related cell adhesion molecule 1; gene expression; evolution; histology; prostate cancer; gleason score; cd16 antigen; androgen receptor; epithelial cell adhesion molecule; cytokeratin 19; cytokeratin; immunocompetent cell; cd14 antigen; peripheral blood mononuclear cell; rna extraction; cd27 antigen; circulating tumor cell; cytokeratin 18; cytokeratin 8; clinical outcome; maximum standardized uptake value; cancer prognosis; metastatic prostate cancer; fluorescence intensity; human; male; article; rna sequencing; lncap cell line; radioligand therapy; tumor mutational burden; receptor type tyrosine protein phosphatase c; lineage transition; vipivotide tetraxetan lutetium lu 177 |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-05-01 |
| Start Page: | 969 |
| End Page: | 987 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-1509 |
| PUBMED: | 39912912 |
| PROVIDER: | scopus |
| PMCID: | PMC12046329 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
