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.