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<p>Malignant tumors are the leading cause of death in individuals over 65 years old, with metastasis as the primary driver. Emerging evidence suggests that age-related metabolic changes and secreted factors increase the risk of metastasis, but the underlying mechanisms remain unclear. Here we demonstrate in mice that extracellular vesicles (EVs) from senescent hepatocytes promote metastasis across tumor types. We show that aged liver tissue exhibits elevated expression of P2X purinoceptor 7 (P2RX7), which is associated with increased EV biogenesis. We identify EV-encapsulated miRNAs (miR-25, miR-92a, miR-30c and miR-30d) that reach primary tumors through the circulation and enhance tumor invasiveness and metastatic potential. Similarly, clinical samples from older patients show reduced expression of the miRNA target genes <i>PTEN</i> and <i>LATS2</i>, as well as enhanced epithelial–mesenchymal transition in metastatic tumors. Therapeutically, targeting senescence with dasatinib and quercetin (D + Q), inhibiting P2RX7, or silencing EV-associated miRNAs considerably reduces metastasis in aged mice. Together, our study uncovers a mechanism by which senescent hepatocyte-derived EVs drive tumor metastasis during aging and highlights potential strategies to mitigate this process.</p>

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Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging

  • 期刊论文

  • 发表日期：

    2026年4月6日

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  • Huilong Li,
  • Ruzhou Zhao,
  • Luming Wan,
  • Yang Yuan,
  • Enhao Ma,
  • Yingang Li,
  • Zhuangzhuang Chen,
  • Binbin Liu,
  • Yurong Song,
  • Ziwei Cao,
  • Xinxin Jiao,
  • Yue Wang,
  • Peng Wu,
  • Hao Jin,
  • Jiatong Li,
  • Xiaopan Yang,
  • Linfei Huang,
  • Yanhong Zhang,
  • Ke Yang,
  • Jiang Huo,
  • Haoran Jin,
  • Hui Zhong,
  • Min Min,
  • Shaohua Zhang,
  • Yuan Cao,
  • Wenlong Li,
  • Rui Zhang,
  • Congwen Wei

摘要

Malignant tumors are the leading cause of death in individuals over 65 years old, with metastasis as the primary driver. Emerging evidence suggests that age-related metabolic changes and secreted factors increase the risk of metastasis, but the underlying mechanisms remain unclear. Here we demonstrate in mice that extracellular vesicles (EVs) from senescent hepatocytes promote metastasis across tumor types. We show that aged liver tissue exhibits elevated expression of P2X purinoceptor 7 (P2RX7), which is associated with increased EV biogenesis. We identify EV-encapsulated miRNAs (miR-25, miR-92a, miR-30c and miR-30d) that reach primary tumors through the circulation and enhance tumor invasiveness and metastatic potential. Similarly, clinical samples from older patients show reduced expression of the miRNA target genes PTEN and LATS2, as well as enhanced epithelial–mesenchymal transition in metastatic tumors. Therapeutically, targeting senescence with dasatinib and quercetin (D + Q), inhibiting P2RX7, or silencing EV-associated miRNAs considerably reduces metastasis in aged mice. Together, our study uncovers a mechanism by which senescent hepatocyte-derived EVs drive tumor metastasis during aging and highlights potential strategies to mitigate this process.