Abstract
Simple SummaryMitochondrial transfer plays a crucial role in the acquisition of drug resistance in multiple myeloma, but its exact mechanism is not yet clear; moreover, overcoming the drug resistance that it causes is also a major challenge. Our research on primary myeloma cell cultures reveals that mitochondrial transfer is bi-directional between bone marrow stromal cells and myeloma cells, occurring via tunneling nanotubes and partial cell fusion with extreme increases under the influence of chemotherapeutic drugs, whereupon survival and adenosine triphosphate levels increase, while mitochondrial superoxide levels decrease in myeloma cells. These changes and the elevation of superoxide levels in stromal cells are proportional to the amount of incorporated mitochondria derived from the other cell type and to the concentration of the used drug. Although the inhibition of mitochondrial transfer is limited between stromal and myeloma cells, the supportive effect of stromal cells can be effectively averted by influencing the tumor metabolism with an inhibitor of oxidative phosphorylation in addition to chemotherapeutics.Recently, it has become evident that mitochondrial transfer (MT) plays a crucial role in the acquisition of cancer drug resistance in many hematologic malignancies; however, for multiple myeloma, there is a need to generate novel data to better understand this mechanism. Here, we show that primary myeloma cells (MMs) respond to an increasing concentration of chemotherapeutic drugs with an increase in the acquisition of mitochondria from autologous bone marrow stromal cells (BM-MSCs), whereupon survival and adenosine triphosphate levels of MMs increase, while the mitochondrial superoxide levels decrease in MMs. These changes are proportional to the amount of incorporated BM-MSC-derived mitochondria and to the concentration of the used drug, but seem independent from the type and mechanism of action of chemotherapeutics. In parallel, BM-MSCs also incorporate an increasing amount of MM cell-derived mitochondria accompanied by an elevation of superoxide levels. Using the therapeutic antibodies Daratumumab, Isatuximab, or Elotuzumab, no similar effect was observed regarding the MT. Our research shows that MT occurs via tunneling nanotubes and partial cell fusion with extreme increases under the influence of chemotherapeutic drugs, but its inhibition is limited. However, the supportive effect of stromal cells can be effectively avoided by influencing the metabolism of myeloma cells with the concomitant use of chemotherapeutic agents and an inhibitor of oxidative phosphorylation.
Highlights
Understanding the molecular mechanisms of cancer drug resistance is critical in order to accomplish effective and long-lasting cancer treatment
To determine the cytotoxicity of different drugs on primary myeloma cell cultures, we examined the effect of various drugs on the viability of myeloma cells and bone marrow stromal cells both in monocultures and BM-mesenchymal stromal cells (MSCs)–MM co-cultures (Figure 1A)
An increased amount of various drugs induced increased cell death of MMs; the surviving cells incorporated an increasing amount of BM-MSC-derived mitochondria (Figure 2C). These results suggest that BM-MSC-derived mitochondria served as a survival signal for the malignant plasma cells, and MMs were more resistant to the cytotoxic effect of the drugs used
Summary
Understanding the molecular mechanisms of cancer drug resistance is critical in order to accomplish effective and long-lasting cancer treatment. The most essential mediators of intercellular signaling are soluble factors, extracellular vesicles, and tunneling nanotubes (TNTs) [2], the interactions of membrane proteins followed by the exchange of large plasma membrane fragments, known as trogocytosis, are decisive in the communication between mesenchymal stromal cells (MSCs) and cancer cells [3]. All of these different types of interactions involve functional interference and the mutual acquisition of new cellular properties.
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