High-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 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, pre-treatment CTC luminal-B-like phenotype was associated with early progression on 177Lu-PSMA-617.
Authors
- Elisabeth I. Heath (ORCID: https://orcid.org/0000-0003-1381-2713)
- Dana E. Rathkopf (ORCID: https://orcid.org/0000-0002-4503-7582)
- Scott T. Tagawa (ORCID: https://orcid.org/0000-0003-2777-8587)
- Joshua M. Lang (ORCID: https://orcid.org/0000-0002-0943-8872)
- Felix Yi-Chung Feng (ORCID: https://orcid.org/0000-0002-0963-7687)
- Katharine E. Tippins
- Hannah M. Krause (ORCID: https://orcid.org/0000-0002-3154-9990)
- Hamid Emamekhoo (ORCID: https://orcid.org/0000-0002-8506-8703)
- Kyle T. Helzer (ORCID: https://orcid.org/0000-0003-3853-5564)
- Alex H. Chang (ORCID: https://orcid.org/0000-0002-8062-1186)
- Andrew J. Armstrong (ORCID: https://orcid.org/0000-0001-7012-1754)
- Martin Sjöström (ORCID: https://orcid.org/0000-0002-2629-9966)
- Xiao X. Wei (ORCID: https://orcid.org/0000-0001-7093-0383)
- Himisha Beltran (ORCID: https://orcid.org/0000-0003-3259-2226)
- Marina N. Sharifi (ORCID: https://orcid.org/0000-0003-0128-3033)
- Menggang Yu (ORCID: https://orcid.org/0000-0002-7904-3155)
- Jamie M. Sperger (ORCID: https://orcid.org/0000-0001-8578-8033)
- Rana R. McKay (ORCID: https://orcid.org/0000-0002-0581-7963)
- Meghan Wells
- Christos E. Kyriakopoulos (ORCID: https://orcid.org/0000-0002-6452-7405)
- Grace C. Blitzer (ORCID: https://orcid.org/0000-0003-3178-3004)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Scott M. Dehm (ORCID: https://orcid.org/0000-0002-7827-5579)
- Atish D. Choudhury (ORCID: https://orcid.org/0000-0001-9344-6631)
- Amy K. Taylor (ORCID: https://orcid.org/0000-0003-4559-4159)
- Matthew L. Bootsma (ORCID: https://orcid.org/0000-0003-0879-5066)
- Shuang George Zhao (ORCID: https://orcid.org/0000-0002-9166-6507)
- David Kosoff (ORCID: https://orcid.org/0000-0001-8559-6357)
- Jennifer L. Schehr (ORCID: https://orcid.org/0000-0003-2123-997X)
- Katherine R. Kaufmann (ORCID: https://orcid.org/0000-0002-5157-9214)
- John M. Floberg (ORCID: https://orcid.org/0000-0002-7635-7554)
- Luke A. Nunamaker
- Charlotte Linebarger
- Leilani Mora-Rodriguez
- Shannon R. Reese (ORCID: https://orcid.org/0000-0002-6760-8876)
- V. Carreño (ORCID: https://orcid.org/0009-0009-3297-8541)
Institutions
- University of Minnesota (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Wisconsin–Madison (US)
- Duke University (US)
- University of California, San Francisco (US)
- Wayne State University (US)
- Lund University (SE)
- University of Washington (US)
- Washington University in St. Louis (US)
- Cornell University (US)
- University of Michigan (US)
- University of Minnesota System (US)
- University of California San Diego (US)
- Fred Hutch Cancer Center (US)
- The Barbara Ann Karmanos Cancer Institute (US)
- University of Wisconsin Carbone Cancer Center (US)
- Prostate Cancer Research (GB)
- Michigan United (US)
- Dana-Farber Cancer Institute (US)
- Mayo Clinic in Arizona (US)
- Skåne University Hospital (SE)
- William S. Middleton Memorial Veterans Hospital (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1158/2159-8290.cd-24-1509
- Citations
- 11
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 16.70
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- University of Wisconsin Carbone Cancer Center
- Movember Foundation
- National Institutes of Health
- Division of Graduate Education