Understanding the interaction between myeloma and the bone marrow niche: role of the Notch pathway in extracellular vesicles-mediated communication

Multiple myeloma (MM) is an incurable hematological tumor stemming from malignant plasma cells. MM cells accumulate in the bone marrow (BM) and establish complex interactions with normal BM stroma, which promotes tumor survival, drug resistance and the development of bone disease. The Notch oncogenic pathway provide a key contribute to the ability of MM cells to shape the BM niche, affecting both MM cell biology and the interplay with the surrounding normal cells. Recently, extracellular vesicles (EVs) have been shown to be crucial for this insidious interaction. This work investigated the effects of Notch inhibition on the EV-mediated crosstalk between neoplastic MM cells and stromal cells, providing evidences that: 1) Notch activity is essential for stroma-derived EVs to promote MM cells migration and drug resistance; 2) MM cells derived EVs are able to activate Notch in stromal cells boosting their ability to secrete pro-tumor factors; 3) Notch is fundamental for MM-derived EVs pro-osteoclastogenic potential. Taken together these results indicate that the Notch pathway promotes the EV-mediated interaction of MM cells and normal BM cells resulting in drug resistance and osteolytic activity, suggesting that a Notch–tailored approach may be effective in targeting the EV-mediated pathological interplay in the BM niche.