Force-feeding malignant mesothelioma stem-cell like with exosome-delivered miR-126 induces tumour cell killing

Malignant pleural mesothelioma (MPM) is an aggressive tumour resistant to treatments. Multimodality treatment is the gold standard therapy at early stage of MPM; however, failure to eradicate in local and/or distant sites is a major concern. It has been postulated that cancer stem cells (CSCs) persist in tumours causing relapse after multimodality treatment. In the present study, a novel miRNA-based therapy approach is proposed. MPM-derived spheroids, which resemble the natural tumours, have been treated with exosome-delivered miR-126 (exo-miR) and evaluated for its anticancer effect. The exo-miR treatment increased MPM stem-cell like stemness and inhibited cell proliferation. However, at prolonged time, the up taken miR-126 was released by the cells themselves through exosomes; the inhibition of exosome release by an exosome release inhibitor GW4869 induced miR-126 intracellular accumulation leading to massive cell death and in vivo tumour growth arrest. Autophagy is involved in these processes; miR-126 accumulation induced a protective autophagy and the inhibition of this process by GW4869 generates a metabolic crisis that promotes necroptosis, which was associated with PARP-1 over-expression and cyt-c and AIF release. In association to the exosome release inhibition, GW4869 showed also a role as inhibitor of autophagy, which is a survival process used by CSCs to evade cancer therapy. Here, for the first time we proposed a therapy against CSCs, a heterogeneous cell population involved in cancer development and relapse.