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.
Molecular oncology. 2025 Feb 22 [Epub ahead of print]
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
Carbone Cancer Center, University of Wisconsin-Madison, WI, USA., Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA., Department of Human Oncology, University of Wisconsin-Madison, WI, USA., Department of Medicine, University of Wisconsin-Madison, WI, USA., Department of Translational Medicine, Lund University, Malmö, Sweden., Department of Diagnostics and Interventions, Urology, Umeå University, Sweden., Department of Medical Biosciences, Pathology, Umeå University, Sweden., Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.