Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer

Marina N Sharifi; Eric Feng; Nicholas R Rydzewski; Amy K Taylor; Jamie M Sperger; Yue Shi; Kyle T Helzer; Matthew L Bootsma; Viridiana Carreno; Alex H Chang; Luke A Nunamaker; Grace C Blitzer; Tianfu Andy Shang; Aishwarya Subramanian; Anders Bjartell; Andreas Josefsson; Pernilla Wikström; Emily Feng; Manish Kohli; Rendong Yang; Scott M Dehm; Eric J Small; Rahul Aggarwal; David A Quigley; Joshua M Lang; Shuang G Zhao; Martin Sjöström

doi:10.1002/1878-0261.70001

Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer

Mol Oncol. 2025 Feb 22. doi: 10.1002/1878-0261.70001. Online ahead of print.

Authors

Marina N Sharifi^{1

2}, Eric Feng^{3

4}, Nicholas R Rydzewski⁵, Amy K Taylor^{1

2}, Jamie M Sperger^{1

2}, Yue Shi⁵, Kyle T Helzer⁵, Matthew L Bootsma⁵, Viridiana Carreno², Alex H Chang², Luke A Nunamaker¹, Grace C Blitzer⁵, Tianfu Andy Shang⁵, Aishwarya Subramanian^{3

4}, Anders Bjartell^{6

7}, Andreas Josefsson^{8

9}, Pernilla Wikström¹⁰, Emily Feng^{3

4}, Manish Kohli¹¹, Rendong Yang¹², Scott M Dehm^{13

14

15}, Eric J Small^{3

16}, Rahul Aggarwal^{3

16}, David A Quigley^{3

17

18}, Joshua M Lang^{1

2}, Shuang G Zhao^{1

5

19}, Martin Sjöström^{3

4

20

21}

Affiliations

¹ Carbone Cancer Center, University of Wisconsin-Madison, WI, USA.
² Department of Medicine, University of Wisconsin-Madison, WI, USA.
³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
⁴ Department of Radiation Oncology, University of California, San Francisco, CA, USA.
⁵ Department of Human Oncology, University of Wisconsin-Madison, WI, USA.
⁶ Department of Translational Medicine, Lund University, Malmö, Sweden.
⁷ Department of Urology, Skåne University Hospital, Malmö, Sweden.
⁸ Department of Diagnostics and Interventions, Urology, Umeå University, Sweden.
⁹ Wallenberg Center for Molecular Medicine, Umeå University, Sweden.
¹⁰ Department of Medical Biosciences, Pathology, Umeå University, Sweden.
¹¹ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹² Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹³ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
¹⁴ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Department of Urology, University of Minnesota, Minneapolis, MN, USA.
¹⁶ Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, CA, USA.
¹⁷ Department of Urology, University of California, San Francisco, CA, USA.
¹⁸ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
¹⁹ William S. Middleton Memorial Veterans' Hospital, Madison, WI, USA.
²⁰ Division of Oncology, Department of Clinical Sciences Lund, Lund University, Sweden.
²¹ Department of Hematology, Oncology, and Radiation Physics, Skåne University Hospital, Lund, Sweden.

PMID: 39985777
DOI: 10.1002/1878-0261.70001

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.

Keywords: biomarker; gene expression; metastatic castration‐resistant prostate cancer; precision medicine; prognosis.

Abstract

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