Scholarlink

<p>The evolution to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic heterogeneity in late-stage disease, we focus on metastatic castration-resistant prostate cancer and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions obtained from 9 patients through rapid autopsy. We find evolutionary convergence of intra-tumour heterogeneity, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. We find little evidence of the microenvironment driving transcriptional heterogeneity, but there are signatures of co-adaptation between the microenvironment and tumour cells. In contrast, clonal evolution primarily foster widespread transcriptional changes that did not result in de novo functional states. Intra-patient functional convergence of tumour ecosystems across metastases indicates system-level selection pressures that drive the heterogeneity landscape of metastatic castration-resistant prostate cancer. Our findings reveal functional evolutionary convergence of metastatic disease into distinct intra-tumour subpopulations, identifying critical determinants for therapeutic targeting.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月19日

查看全文
  • Sirui Weng,
  • Lachlan Cain,
  • James Comben,
  • Yangyi Zhang,
  • Timothy Semple,
  • Sara Alaei,
  • David Yoannidis,
  • Luciano Martelotto,
  • Catherine Mitchell,
  • Anupama Pasam,
  • Richard J. Young,
  • Benjamin Blyth,
  • Joy Hendley,
  • Yuzhou Feng,
  • Heather Thorne,
  • Roslyn Wallace,
  • Joanna Chan,
  • Julia Como,
  • Lisa Devereux,
  • Himisha Beltran,
  • Daniel Wetterskog,
  • Scott Williams,
  • Anthony T. Papenfuss,
  • Belinda Parker,
  • Paul Neeson,
  • Gerhardt Attard,
  • David Quigley,
  • David L. Goode,
  • Richard B. Pearson,
  • Luc Furic,
  • Anna S. Trigos,
  • Shahneen Sandhu

摘要

The evolution to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic heterogeneity in late-stage disease, we focus on metastatic castration-resistant prostate cancer and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions obtained from 9 patients through rapid autopsy. We find evolutionary convergence of intra-tumour heterogeneity, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. We find little evidence of the microenvironment driving transcriptional heterogeneity, but there are signatures of co-adaptation between the microenvironment and tumour cells. In contrast, clonal evolution primarily foster widespread transcriptional changes that did not result in de novo functional states. Intra-patient functional convergence of tumour ecosystems across metastases indicates system-level selection pressures that drive the heterogeneity landscape of metastatic castration-resistant prostate cancer. Our findings reveal functional evolutionary convergence of metastatic disease into distinct intra-tumour subpopulations, identifying critical determinants for therapeutic targeting.