Alvarez-Velez, R. | Search bioRxiv

bioRxiv2026

Extracellular Vesicles from Senescent Tumor Cells Are Necessary and Sufficient to Drive Paracrine Senescence

Cellular senescence exerts powerful non-cell autonomous effects through the senescencelzlassociated secretory phenotype (SASP). This SASP comprises soluble factors and extracellular vesicles (EVs). Although soluble SASP components can induce senescence in neigbouring 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 bleomycinlzlinduced senescent A549 cells triggered a permanent 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 therapylzlinduced senescence.

cancer biology↗

bioRxiv2024

Deficient Memory, Long-Term Potentiation and Hippocampal Synaptic Plasticity in Galectin-4-KO Mice.

BACKGROUNDBrain function is influenced by the gut through the microbiota-gut-brain axis. Non-physiological microbiota-depletion or induced gut infection in animal models, have been instrumental to link intestinal alterations to cognitive and mood dysfunctions. However, the effects of specific, controlled, physiologically relevant shifts in commensal microbiota composition on brain function remain poorly understood. METHODSMice deficient in galectin-4 (Lgals4-KO) were used in this study. Gut microbiota was analysed by 16S-rRNA sequencing. Cognitive and mood status were evaluated with specific behavioral tests. Long-term potentiation (LTP) was tested ex vivo and in vivo by electrophysiological methods and in vitro by immunofluorescence and western blot. RNA-sequencing was used for transcriptomic analyses. Golgi-Cox staining and transmission electron microscopy were used for quantitative and morphological assessments of dendritic spines and synapses. RESULTSLgals4-KO mice present an altered intestinal commensal microbiota in the absence of pathogens, deficient memory formation, and impaired hippocampal LTP in vivo and ex vivo. Furthermore, Lgals4-KO neurons show a reduced activation of AMPA receptors and of CaMKII upon chemically induced LTP in vitro. These mice also display significantly lower dendritic spine density and shorter spine length in hippocampal dendrites, as well as an increased area of the postsynaptic densities CONCLUSIONSOur results define a new role for galectin-4 in the modulation of commensal bacteria. We also show that the absence of galectin-4 induces changes in gut microbial composition, along with synaptic alterations and memory impairment, supporting our hypothesis that variations in endogenous microbiota may cause or contribute to relevant neurological pathologies.

neuroscience↗