Osteocyte-derived exosomes confer multiple myeloma resistance to chemotherapy through acquisition of cancer stem cell-like features

Abstract Therapeutic resistance is a major challenge in multiple myeloma treatment. Understanding the underlying mechanisms is required to develop effective strategies against drug resistance and improve the prognosis of myeloma patients. Here, we identify osteocytes, the major cellular component of bone tissue, as key regulators of myeloma therapeutic resistance. Osteocyte-derived exosomes can be efficiently taken up by myeloma cells and exert a protective effect against chemotherapy-induced apoptosis. Mechanistic studies further reveal that osteocyte-derived exosomal miR-483-3p and miR-513a-5p promote cancer stem cell-like features in myeloma cells by regulating HIF-1α stabilization, thus conferring myeloma cells resistance to chemotherapy. Strikingly, combination treatment of miR-483-3p and miR-513a-5p inhibitors significantly reduces tumor burden and potentiates the therapeutic efficacy of bortezomib in the myeloma mouse model. Our findings, therefore, demonstrate the functional impact of osteocytes on myeloma therapeutic resistance, and suggest that osteocyte-derived exosomal miRNAs may serve as potential therapeutic targets for overcoming drug resistance in multiple myeloma.