Tumour-derived extracellular vesicles within the therapy-induced senescent secretome distinctly suppress breast cancer via DKK1-mediated inflammatory response

Abstract

ABSTRACTTriple-negative breast cancers (TNBC), associated with poor prognosis and high tumour recurrence, are often-treated with taxanes in first-line treatment regimens. However, acquired disease resistance can often set in, hampering clinical efficacy. One avenue that could engender therapy resistance is therapy-induced senescence (TIS), as they represent a population of residual disease and are highly secretory. Although it is known that TIS can contribute to tumour development and therapy resistance via the therapy-induced secretome, the underlying molecular mechanisms are not fully understood. In this study, we sought to dissect the role of the TNBC-derived TIS-associated secretome in chemoresponse. We found that paclitaxel-treated cells induced mitotic slippage and entered senescence as tetraploid cells. The therapy-induced SASP was found to be enriched in soluble cytokines and other pro-tumorigenic factors linked to tumour recurrence and distant metastasis. Interestingly, we found that senescence-associated small extracellular vesicles (sEVs) or exosomes, an underappreciated component of SASP, increased genomic instability, ROS and anti-tumour activity. Exosomal proteomic and transcriptomic profiling further revealed DKK1, a negative regulator of WNT signalling, to be enriched in TIS-sEVs. Further investigation demonstrated DKK1-control of inflammatory cytokines production to confer reduced tumour activity in recipient TNBC cancer cells. Taken together, this study revealed unexpected findings where TIS-sEVs confer opposing tumourigenic outcomes to that elicited by TIS-SASP, indicating that sEVs should be considered as distinct SASP entities.