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<p>Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD<sup>+</sup>–SIRT–SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.</p>

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The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Aidan R. Cole,
  • Raquel Buj,
  • Apoorva Uboveja,
  • Evan Levasseur,
  • Alexander Tom,
  • Hui Wang,
  • Katarzyna M. Kedziora,
  • Adam Chatoff,
  • Andrea Andress Huacachino,
  • Mariola M. Marcinkiewicz,
  • Amandine Amalric,
  • Baixue Yang,
  • Naveen Kumar Tangudu,
  • Emily Noonan,
  • Jeff Danielson,
  • Miho Naruse,
  • Amal Taher Elhaw,
  • Sierra White,
  • Danyang Li,
  • Callen T. Wallace,
  • Frederick Keeney,
  • Felicia Lazure,
  • Esther Elishaev,
  • Lauren Borho,
  • Hope A. Townsend,
  • Robin D. Dowell,
  • Aaron Clauset,
  • Dorota E. Jazwinska,
  • Matthew S. Laird,
  • Huda Atiya,
  • Denarda Dangaj,
  • Lan G. Coffman,
  • George Tseng,
  • Steffi Oesterreich,
  • Andrew Kossenkov,
  • Qin Liu,
  • Ana P. Gomes,
  • Aditi U. Gurkar,
  • Francisco J. Schopfer,
  • Francesmary Modugno,
  • Simon C. Watkins,
  • Ioannis K. Zervantonakis,
  • Benjamin G. Bitler,
  • Wayne Stallaert,
  • Nadine Hempel,
  • Nathaniel W. Snyder,
  • Katherine M. Aird

摘要

Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+–SIRT–SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.