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.

Hereditary renal tubulopathies are rare monogenic disorders caused by defects in tubular transport mechanisms that impair the handling of electrolytes, water, and acid–base balance along the nephron. While each tubulopathy is individually uncommon, their collective burden is clinically relevant, as these disorders can severely affect quality of life and predispose to nephrolithiasis, dehydration episodes, and progression to chronic kidney disease. Advances in molecular genetics have identified more than 70 genes involved in renal tubular physiology; however, a substantial proportion of these cases remain genetically unresolved, and marked phenotypic heterogeneity complicates diagnosis and management. This narrative review provides an integrated overview of the main transport systems operating in the different tubular segments of the nephron—proximal tubule, thick ascending limb of the loop of Henle, distal convoluted tubule and collecting duct—summarizing the tubulopathies associated with each segment and discussing in greater detail representative inherited disorders that illustrate the clinical consequences of their dysfunction. We highlight current diagnostic challenges and limitations of existing therapeutic strategies and discuss novel diagnostic approaches as well as emerging treatment options. Improved genetic diagnosis, validation of candidate biomarkers, and the development of novel therapeutic strategies will be essential to advance precision medicine and improve outcomes for patients with inherited renal tubulopathies.

Cell reprogramming to pluripotency applied to the study of cancer has identified transformation and pluripotency as two independent and incompatible cell fates. A detailed knowledge of the relationship between transformation and reprogramming could lead to the identification of new vulnerabilities and therapeutic targets in cancer. Here, we explore this interplay and find that OSKM expression limits tumor cell growth by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that OSKM expression impairs tumor growth and reduces tumor burden.

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.

During cancer development and progression, many genetic alterations lead to the acquisition of novel features that confer selective advantage to cancer cells and that resemble developmental programs. SOX2 is one of the key pluripotency transcription factors, expressed during embryonic development and active in adult stem cells. In cancer, SOX2 is frequently dysregulated and associated with tumor stemness and poor patient survival. SOX2 expression is suppressed in differentiated cells by tumor suppressor proteins that form a transcriptional repressive complex. We previously identified some of these proteins and found that their absence combined with deficiency in Trp53, leads to maximal dysregulated expression of Sox2. Using cancer cell lines of different origin and with different p53 status, we show here that manipulating TP53 to restore or decrease its activity results in repression or induction of SOX2, respectively. Mechanistically, we observed that the regulation of SOX2 expression by TP53 is transcriptional and identified Trp53 bound to the promoter region and the SRR2 enhancer of Sox2. Forcing high levels of SOX2 in cancer cells leads to morphological changes that molecularly correspond to the acquisition of a more mesenchymal phenotype correlating with an increased migratory capacity. Finally, the analysis of human breast cancer samples shows that this correlation between TP53 status, levels of expression of SOX2 and a more metastatic phenotype is also observed in cancer patients. Our results support the notion that lack of TP53 in tumor cells results in deregulated expression of developmental gene SOX2 with phenotypic consequences related with increased malignization.

Partial reprogramming has emerged as a promising strategy to ameliorate aging phenotypes, yet its cellular targets and mechanisms remain poorly defined. Cellular senescence is a central hallmark of aging and a plausible mediator of reprogramming-induced rejuvenation. Here we show that genetic and chemical partial reprogramming act directly on senescent cells without restoring proliferative capacity. OSKM expression or a reduced two-compound regimen, tranylcypromine and RepSox (2c), attenuates senescence-associated secretory activity, restores mitochondrial homeostasis and apoptotic priming, and improves functional and inflammatory parameters in aged mice, establishing senomorphic, identity-preserving reprogramming as a potentially safer aging intervention.