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<p>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.</p>

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Clonal evolution and transcriptional plasticity shape metastatic dissemination routes in prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Migle Mikutenaite,
  • Evdoxia Karadoulama,
  • Francesco Favero,
  • Alessio Locallo,
  • Francisco German Rodriguez Gonzalez,
  • Daria Kiriy,
  • Tina Keshavarzian,
  • Kira Furlano,
  • Markus Graefen,
  • Robert G. Bristow,
  • Clarissa Gerhäuser,
  • Christoph Plass,
  • Guido Sauter,
  • Ronald Simon,
  • Mathieu Lupien,
  • Sarah Minner,
  • Thorsten Schlomm,
  • Joachim Weischenfeldt

摘要

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.