Extracellular vesicles within a tumourigenic therapy-induced senescent tumour secretome are able to confer anti-cancer properties

Cellular senescence is a fundamental response against chemotherapy to avoid cell death, and the resulting therapy-induced senescent (TIS) cells have been associated with cancer recurrence and therapy resistance via its paracrine activity. The paracrine activity of TIS cells is heavily influenced by the composition and dynamics of the senescence associated secretory phenotype (SASP). The SASP itself is known to be predominantly composed by soluble cytokines, chemokines, and growth factors. The non-soluble fraction of SASP, specifically small extracellular vesicles (sEVs), represents an underappreciated component of SASP and are still poorly characterized. Here we show that the SASP may mediate tumor recurrence and distant metastasis in mice, as well as support invasive and migratory behavior in-vitro . Remarkably, while the SASP itself may be pro-tumorigenic, we found that therapy-induced senescent sEVs isolated from the SASP are able to reduce syngeneic tumor growth in-vivo . Transcriptomic analysis from therapy-induced sEV recipient mice tissue revealed downregulation of proliferation and mitotic pathways, akin to a senescence-like phenotype, along with upregulation of inflammatory and antigen-presentation pathways. Further characterization revealed that TIS sEVs recipient cells are less invasive and migratory, and that they also exhibit elevated level of reactive oxygen species (ROS), concomitantly with sustained γ-H2AX expression and micronuclei generation. Our results indicate that therapy-induced senescent cancer cell-derived sEVs should be considered as distinct SASP entities.