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<p>Despite the high prevalence of ERG transcription factor translocations in prostate cancer, the mechanism of tumorigenicity remains poorly understood. Using lineage tracing, we find the tumor-initiating activity of ERG resides in a subpopulation of murine basal cells that coexpress luminal genes (Basal<sup>Lum</sup>) and not in the larger population of ERG<sup>+</sup> luminal cells. Upon ERG activation, Basal<sup>Lum</sup> cells give rise to highly proliferative intermediate (IM) cells with stem-like features that coexpress basal, luminal, hillock and club marker genes, before transitioning to Krt8<sup>+</sup> luminal cells. Transcriptomic analysis of ERG<sup>+</sup> human prostate cancers confirms the presence of rare ERG<sup>+</sup> Basal<sup>Lum</sup> cells, as well as IM cells whose presence is associated with a worse prognosis. Single-cell analysis revealed a chromatin state in ERG<sup>+</sup> IM cells enriched for STAT3 transcription factor binding sites and elevated expression of the KMT2A/MLL1 and DOT1L, all three of which are essential for ERG-driven tumorigenicity in vivo. In addition to providing translational opportunities, this work illustrates how single-cell approaches combined with lineage tracing can identify cancer vulnerabilities not evident from bulk analysis.</p>

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ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • Weiran Feng,
  • Erik Ladewig,
  • Matthew Lange,
  • Nazifa Salsabeel,
  • Huiyong Zhao,
  • Young Sun Lee,
  • Anuradha Gopalan,
  • Hanzhi Luo,
  • Wenfei Kang,
  • Ning Fan,
  • Eric Rosiek,
  • Elisa de Stanchina,
  • Yu Chen,
  • Brett S. Carver,
  • Christina S. Leslie,
  • Charles L. Sawyers

摘要

Despite the high prevalence of ERG transcription factor translocations in prostate cancer, the mechanism of tumorigenicity remains poorly understood. Using lineage tracing, we find the tumor-initiating activity of ERG resides in a subpopulation of murine basal cells that coexpress luminal genes (BasalLum) and not in the larger population of ERG+ luminal cells. Upon ERG activation, BasalLum cells give rise to highly proliferative intermediate (IM) cells with stem-like features that coexpress basal, luminal, hillock and club marker genes, before transitioning to Krt8+ luminal cells. Transcriptomic analysis of ERG+ human prostate cancers confirms the presence of rare ERG+ BasalLum cells, as well as IM cells whose presence is associated with a worse prognosis. Single-cell analysis revealed a chromatin state in ERG+ IM cells enriched for STAT3 transcription factor binding sites and elevated expression of the KMT2A/MLL1 and DOT1L, all three of which are essential for ERG-driven tumorigenicity in vivo. In addition to providing translational opportunities, this work illustrates how single-cell approaches combined with lineage tracing can identify cancer vulnerabilities not evident from bulk analysis.