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<p>Sarcopenia is an age-related condition characterized by loss of skeletal muscle mass and strength and is associated with increased cancer incidence and mortality, yet how muscle decline promotes tumorigenesis remains unclear. Here, we show that skeletal muscle functions as an anti-tumor organ by secreting extracellular vesicles (EVs) that suppress tumor growth. Using <i>Drosophila melanogaster</i> and mouse cancer models, we demonstrate that muscle-derived EVs inhibit tumorigenesis. In contrast, sarcopenic muscle exhibits reduced EV secretion and altered EV cargo, resulting in loss of tumor-suppressive activity. We identify miR-7a-5p as a tumor-suppressive microRNA enriched in EVs from healthy muscle but diminished with aging, where it restrains tumor growth by inhibiting TEAD1 signaling. Mechanistically, muscle EV biogenesis is regulated by a NOTCH–SDC2 pathway that declines with age but is reactivated by exercise. Together, these findings define a muscle-to-tumor communication axis with therapeutic potential.</p>

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Sarcopenia promotes tumorigenesis by disrupting NOTCH-SDC2-regulated biogenesis of muscle-derived extracellular vesicles

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月27日

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  • Kah Yong Goh,
  • Wen Xing Lee,
  • Qian Gou,
  • Sze Mun Choy,
  • Shi Chee Ong,
  • Priya D. Gopal Krishnan,
  • Huaxin Wang,
  • Lewin Raymarc Roldan Turqueza,
  • Qian Hui Tan,
  • Kenon Chua,
  • Shang Li,
  • Jun Nishiyama,
  • Nathan Harmston,
  • Hong-Wen Tang

摘要

Sarcopenia is an age-related condition characterized by loss of skeletal muscle mass and strength and is associated with increased cancer incidence and mortality, yet how muscle decline promotes tumorigenesis remains unclear. Here, we show that skeletal muscle functions as an anti-tumor organ by secreting extracellular vesicles (EVs) that suppress tumor growth. Using Drosophila melanogaster and mouse cancer models, we demonstrate that muscle-derived EVs inhibit tumorigenesis. In contrast, sarcopenic muscle exhibits reduced EV secretion and altered EV cargo, resulting in loss of tumor-suppressive activity. We identify miR-7a-5p as a tumor-suppressive microRNA enriched in EVs from healthy muscle but diminished with aging, where it restrains tumor growth by inhibiting TEAD1 signaling. Mechanistically, muscle EV biogenesis is regulated by a NOTCH–SDC2 pathway that declines with age but is reactivated by exercise. Together, these findings define a muscle-to-tumor communication axis with therapeutic potential.