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Background <p>Castration-resistant prostate cancer (CRPC) frequently emerges after androgen deprivation therapy (ADT), yet the early tumor-cell states that support this transition remain incompletely understood. Liquid–liquid phase separation (LLPS) has recently been implicated in prostate cancer progression, but its contribution to early AR-independent adaptation remains unclear.</p> Methods <p>We integrated bulk transcriptomic, single-cell transcriptomic, LLPS-related gene, and experimental validation analyses to identify LLPS-associated molecular features linked to CRPC progression. Candidate genes and tumor-cell states were prioritized using machine-learning-based signature construction, single-cell subpopulation analysis, in vitro phase-separation assays, functional experiments, in silico perturbation, and structure-based compound screening.</p> Results <p>An LLPS-related five-gene signature distinguished CRPC-associated transcriptomic states across independent cohorts, with CLEC2D emerging as the most prominently upregulated candidate. Single-cell analysis revealed a distinct CLEC2D⁺AR⁻ malignant tumor-cell population enriched in short-term ADT-treated CSPC samples and characterized by reduced AR activity, proliferative and metastatic programs, and enhanced communication with stromal and immunomodulatory cell populations. Experimentally, CLEC2D formed dynamic condensates through its N-terminal intrinsically disordered region, and CLEC2D overexpression promoted prostate cancer cell proliferation and migration, with these effects being partially attenuated by IDR deletion. In silico CLEC2D perturbation further suggested altered IL-2/STAT5-related signaling, while structure-based screening identified Bilobetin as a potential CLEC2D-interacting compound.</p> Conclusions <p>This study identifies an LLPS-associated CLEC2D⁺AR⁻ tumor-cell state that may participate in early adaptive progression under androgen-targeted pressure. These findings provide a conceptual link between LLPS biology, AR-independent tumor-cell plasticity, and microenvironmental remodeling in CRPC, while nominating CLEC2D as a candidate marker and potential therapeutic target requiring further experimental validation.</p>

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Integrative multi-omics analysis reveals LLPS-associated CLEC2D⁺AR⁻ tumor-cell states linked to early adaptive progression toward castration resistance in prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Zekun Cheng,
  • Jinhua Yan,
  • Shunkang Xue,
  • Yikai Zhang,
  • Zehao Cheng,
  • Lin Xiao,
  • Hao Jiang,
  • Shumiao Zhang,
  • Rong Gui,
  • Shubing Zhang,
  • Rong Gui

摘要

Background

Castration-resistant prostate cancer (CRPC) frequently emerges after androgen deprivation therapy (ADT), yet the early tumor-cell states that support this transition remain incompletely understood. Liquid–liquid phase separation (LLPS) has recently been implicated in prostate cancer progression, but its contribution to early AR-independent adaptation remains unclear.

Methods

We integrated bulk transcriptomic, single-cell transcriptomic, LLPS-related gene, and experimental validation analyses to identify LLPS-associated molecular features linked to CRPC progression. Candidate genes and tumor-cell states were prioritized using machine-learning-based signature construction, single-cell subpopulation analysis, in vitro phase-separation assays, functional experiments, in silico perturbation, and structure-based compound screening.

Results

An LLPS-related five-gene signature distinguished CRPC-associated transcriptomic states across independent cohorts, with CLEC2D emerging as the most prominently upregulated candidate. Single-cell analysis revealed a distinct CLEC2D⁺AR⁻ malignant tumor-cell population enriched in short-term ADT-treated CSPC samples and characterized by reduced AR activity, proliferative and metastatic programs, and enhanced communication with stromal and immunomodulatory cell populations. Experimentally, CLEC2D formed dynamic condensates through its N-terminal intrinsically disordered region, and CLEC2D overexpression promoted prostate cancer cell proliferation and migration, with these effects being partially attenuated by IDR deletion. In silico CLEC2D perturbation further suggested altered IL-2/STAT5-related signaling, while structure-based screening identified Bilobetin as a potential CLEC2D-interacting compound.

Conclusions

This study identifies an LLPS-associated CLEC2D⁺AR⁻ tumor-cell state that may participate in early adaptive progression under androgen-targeted pressure. These findings provide a conceptual link between LLPS biology, AR-independent tumor-cell plasticity, and microenvironmental remodeling in CRPC, while nominating CLEC2D as a candidate marker and potential therapeutic target requiring further experimental validation.