Clonal evolution and transcriptional plasticity shape metastatic dissemination routes in prostate cancer
Prostate cancer is a highly heterogeneous disease, driven by genomic and transcriptional changes that impact disease progression and metastatic potential. The interplay between clonal evolution, transcriptional plasticity, and tumour microenvironment is, however, poorly understood. Here, we leverage and integrate single-nuclei RNA sequencing and whole-genome sequencing from 43 spatially distinct tumour samples from five patients with locally advanced prostate cancer to reconstruct clonal evolution trajectories and transcriptional changes driving metastasis at single-cell resolution. We find extensive clonal heterogeneity, including both monophyletic and polyphyletic metastatic dissemination, and ongoing clonal evolution in the primary tumour after metastatic spread. Metastatic seeding converges on disease trajectories involving both genomic and transcriptional changes, including androgen receptor independence and activation of estrogen-, WNT- and JAK-STAT- pathway activity, in spatially distinct areas. Our findings suggest an intricate interplay between clonal evolution and cellular plasticity driving metastatic seeding and point toward more integrative prognostic markers for improved patient management.
Authors
- Mathieu Lupien (ORCID: https://orcid.org/0000-0003-0929-9478)
- F. G. Rodriguez Gonzalez
- Daria Kiriy (ORCID: https://orcid.org/0000-0002-8925-7798)
- S. Minner
- Tina Keshavarzian (ORCID: https://orcid.org/0000-0003-3254-3205)
- CLARISSA GERHÄUSER
- J. Weischenfeldt
- Kira Furlano (ORCID: https://orcid.org/0000-0003-1724-7061)
- Migle Mikutenaite (ORCID: https://orcid.org/0000-0002-3531-6465)
- Evdoxia Karadoulama
- Ronald Simon (ORCID: https://orcid.org/0000-0003-0158-4258)
- Alessio Locallo (ORCID: https://orcid.org/0000-0003-0977-9586)
- Markus Graefen
- Thorsten Schlomm
- Guido Sauter
- Robert G. Bristow
- Francesco Favero
- Christoph Plass
Institutions
- Ontario Institute for Cancer Research (CA)
- University of Copenhagen (DK)
- University Health Network (CA)
- Universität Hamburg (DE)
- German Cancer Research Center (DE)
- University of Toronto (CA)
- Heidelberg University (DE)
- Copenhagen University Hospital (DK)
- Princess Margaret Cancer Centre (CA)
- Rigshospitalet (DK)
- University Medical Center Hamburg-Eppendorf (DE)
- Martini-Klinik (DE)
- Cancer Research UK Manchester Institute (GB)
- The Christie NHS Foundation Trust (GB)
- Charité - Universitätsmedizin Berlin (DE)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-23
- DOI
- https://doi.org/10.1038/s41467-025-66704-w
- Citations
- 1
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Princess Margaret Cancer Foundation
- Government of Ontario
- Bundesministerium für Bildung und Forschung
- Novo Nordisk
- Novo Nordisk Fonden
- Canadian Institutes of Health Research