Scholarlink

<p>Cancer cells avert apoptosis to sustain growth, evade immunity, and resist therapy. However, how they escape specific extrinsic death signals remains unclear. We show that certain epithelial carcinomas co-opt the death-receptor ligand Apo2L/TRAIL to suppress apoptosis while acquiring killing capacity. Analysis of CRISPR knockout screens from the Cancer Dependency Map uniquely&#xa0;identified TRAIL as an essential tumor necrosis factor superfamily member in epithelial malignancies. Renal cell carcinomas (RCC) and squamous cell carcinomas (SCC) expressed TRAIL within both malignant and nonmalignant compartments. In RCC, loss of the tumor suppressor VHL induced HIF2α-dependent TRAIL transcription, whereas in SCC, 3q26 amplification increased TRAIL abundance. Fractional TRAIL silencing revealed killing of TRAIL-deficient cells by TRAIL-expressing counterparts, while full silencing sensitized cells to extrinsic TRAIL. Mechanistically, endogenous TRAIL suppressed apoptosis through lysosomal degradation of its cognate death receptors. Thus, cancer cells can repurpose TRAIL via a surprising apoptotic “cloak-and-dagger” mechanism with significant therapeutic potential.</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

Epithelial cancer cells co-opt the death ligand TRAIL to avert extrinsic apoptosis while acquiring killing capacity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月9日

查看全文
  • John Canty,
  • Scot Marsters,
  • David Lawrence,
  • Serena Lee,
  • Hartmut Koeppen,
  • Avi Ashkenazi

摘要

Cancer cells avert apoptosis to sustain growth, evade immunity, and resist therapy. However, how they escape specific extrinsic death signals remains unclear. We show that certain epithelial carcinomas co-opt the death-receptor ligand Apo2L/TRAIL to suppress apoptosis while acquiring killing capacity. Analysis of CRISPR knockout screens from the Cancer Dependency Map uniquely identified TRAIL as an essential tumor necrosis factor superfamily member in epithelial malignancies. Renal cell carcinomas (RCC) and squamous cell carcinomas (SCC) expressed TRAIL within both malignant and nonmalignant compartments. In RCC, loss of the tumor suppressor VHL induced HIF2α-dependent TRAIL transcription, whereas in SCC, 3q26 amplification increased TRAIL abundance. Fractional TRAIL silencing revealed killing of TRAIL-deficient cells by TRAIL-expressing counterparts, while full silencing sensitized cells to extrinsic TRAIL. Mechanistically, endogenous TRAIL suppressed apoptosis through lysosomal degradation of its cognate death receptors. Thus, cancer cells can repurpose TRAIL via a surprising apoptotic “cloak-and-dagger” mechanism with significant therapeutic potential.