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

Authors

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

Published in

Nature aging. Jul 30, 2026. Epub Jul 30, 2026.

Abstract

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.

PMID:
42533106
Bibliographic data and abstract were imported from PubMed on 31 Jul 2026.

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