Force-feeding malignant mesothelioma stem-cell like with exosome-delivered miR-126 induces tumour cell killing
Mesothelioma
0303 health sciences
miRNA-based therapy
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
spheroids
miR-126
3. Good health
03 medical and health sciences
Mesothelioma; miR-126; exosome; spheroids; miRNA-based therapy
spheroid
exosome
RC254-282
Original Research
DOI:
10.1016/j.tranon.2022.101400
Publication Date:
2022-03-23T03:50:57Z
AUTHORS (13)
ABSTRACT
Malignant pleural mesothelioma (MPM) is an aggressive tumour resistant to treatments. 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 have been treated with exosome-delivered miR-126 (exo-miR) and evaluated for their anticancer effect. The exo-miR treatment increased MPM stem-cell like stemness and inhibited cell proliferation. However, at a 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. Here, for the first time, we proposed a therapy against CSCs, a heterogeneous cell population involved in cancer development and relapse.
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