Extracellular Vesicles From Senescent Cancer Cells Are Necessary and Sufficient to Drive Paracrine Senescence.

Authors

Valentin Estevez-Souto, Alex Miralles-Dominguez, Pablo Pedrosa, Patricia Lado-Fernandez, Miguel A Prados, Alejandro Failde-Fiestras, Raquel Paredes-Paredes, Jorge Ruz-Ortega, Maria J Alonso, Martina Migliavacca, Ester Polo, Rebeca Alvarez-Velez, Enrique Vazquez de Luis, Ana Dopazo, Gabriela N Condezo, Carmen San Martin, Miguel Gonzalez-Barcia, Ramón Lobato-Busto, Pilar Ximénez-Embún, Javier Muñoz, Manuel Collado, Sabela Da Silva-Alvarez

Published in

Aging cell. Volume 25. Issue 10. Pages e70722.

Abstract

Cellular senescence exerts powerful non-cell autonomous effects through the senescence-associated secretory phenotype (SASP). This SASP comprises soluble factors and extracellular vesicles (EVs). Although soluble SASP components can induce senescence in neighboring cells, the specific contribution of EVs to paracrine senescence is poorly defined. Here, we show that EVs released by senescent tumor cells are necessary and sufficient to propagate senescence. Conditioned media from bleomycin-induced senescent A549 cells triggered a growth arrest with morphological changes and upregulation of senescence markers in recipient tumor cells. Pharmacological inhibition of EV biogenesis using GW4869 or genetic downregulation of the EV secretion mediator RAB27A markedly attenuates paracrine senescence without affecting soluble SASP factor secretion or the senescent state of producer cells. Proteomic characterization reveals that senescent EVs exhibit a distinct molecular signature enriched for extracellular components and processes related to wound healing and hemostasis. Importantly, purified senescent EVs, devoid of soluble SASP factors, fully recapitulated paracrine senescence induction. These findings identify senescent EVs as key autonomous SASP effectors and highlight vesicular pathways as potential therapeutic targets in cancer and therapy-induced senescence.

PMID:
42775649
Bibliographic data and abstract were imported from PubMed on 23 Sep 2026.

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