Prostate cancer is among the most prevalent malignancies in men and a leading cause of cancer mortality worldwide. While localized prostate cancer is often curable, progression to metastatic and castration-resistant disease either in lymph nodes or bone/bone marrow remains the major cause of death. Understanding the genomic events that drive metastasis-particularly in treatment-naïve patients-is critical to improving early detection and individualized therapy. Bulk tumor sequencing has revealed key mutational signatures but cannot resolve the cellular heterogeneity and clonal dynamics underlying metastatic spread. Single-cell genomic approaches now enable high-resolution dissection of tumor evolution, uncovering the diversity of cancer clones across disease sites.
We performed whole-genome and whole-exome sequencing on single cancer cells from a treatment-naïve patient with metastatic prostate cancer, isolating cells from the primary tumor, circulating tumor cells (CTCs), disseminated tumor cells (DTCs) in bone marrow, and metastatic bone lesions. Copy number aberrations (CNAs) and single-nucleotide variants (SNVs) were characterized to define genomic heterogeneity and infer clonal relationships. Frequent monoallelic losses in tumor suppressors (PTEN, TP53, FOXO4, STAG2) and gains in oncogenes (MTOR, RAF1, HRAS) and an angiogenic growth factor (VEGFB), were observed. Metastatic cells displayed fewer genomic alterations than CTCs or DTCs. While this observation is consistent with the hypothesis that metastatic competence may be associated with relative genomic stability, normal cell contamination of the metastatic biopsy cannot be excluded, and this interpretation should be considered preliminary. Clonal evolution analysis revealed a complex branching pattern consistent with multidirectional dissemination, suggesting bidirectional seeding between the primary tumor, circulation, and metastatic sites as one possible model of spread, though alternative explanations including phylogenetic reconstruction artefacts cannot be excluded from a single-patient study.
This study provides a single-cell genomic map of metastatic prostate cancer from a treatment-naïve patient, highlighting the coexistence of diverse subclones across disease sites and supporting a multidirectional model of cancer spread.These findings raise the hypothesis that metastatic progression can emerge from multiple subclones with distinct CNA and SNV profiles. Single-cell genomic profiling of untreated tumors represents a promising approach to reconstruct clonal evolution and inform precision therapies targeting early metastatic lineages, though validation in larger patient cohorts will be required.
Not applicable.
BMC genomic data. 2026 May 08 [Epub ahead of print]
Juan Jovel, Bernhard Polzer, Jordan Patterson, Hou Yong, Catalina Vasquez, Sandra O'keefe, Desmond Pink, Guibo Li, Adrian Fairey, Benjamin Adam, Jeremy Teitelbaum, Amir Salimi, Stefan Kirsh, Barbara Alberter, Lori Lowes, Eric Carpenter, Michael Kolinsky, Zhongyi Zhu, Qing Zhou, Peter Venner, Christopher Venner, David Williams, Alison Allan, Paul C Boutros, Christoph A Klein, Gane Wong, John D Lewis
Office of Research, University of Alberta, Edmonton, AB, T6C 4G9, Canada., Fraunhofer Institute for Toxicology and Experimental Medicine, 93053, Regensburg, Germany., Department of Medicine, University of Alberta, Edmonton, AB, T6G 1Z1, Canada., BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, China., Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton, AB, T6G 2E1, Canada., Department of Surgery, University of Alberta, Edmonton, AB, Canada., Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada., Department of Mathematics, University of Connecticut, Storrs, CT, USA., Department of Computing Science, University of Alberta, Edmonton, AB, Canada., Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany., Department of Anatomy and Cell Biology, Western University, London, ON, Canada., Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada., Department of Human Genetics & Urology, University of California, Los Angeles, CA, USA., Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton, AB, T6G 2E1, Canada. .