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The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming
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DOI：10.1038/s43587-026-01172-5.png)
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Abstract
En 中文
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. Cole and colleagues identify fructose as a component of the secretome in therapy-induced senescent ovarian cancer cells that drives metastasis. Fructose metabolically reprograms neighboring cancer cells, enhancing their ability to detach by reducing plasma membrane cholesterol through modulation of complex I and NAD.
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