Stromal Cells Serve Drug Resistance for Multiple Myeloma via Mitochondrial Transfer: A Study on Primary Myeloma and Stromal Cells

Abstract

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.

Cell-Projection Pumping of Fibroblast Contents into Osteosarcoma SAOS-2 Cells Correlates with Increased SAOS-2 Proliferation and Migration, as well as Altered Morphology

“…We earlier described the exchange of membrane, organelles and cytoplasmic protein between cultured human fibroblasts and cancer cells [ 1 , 2 , 3 ] and others have made similar observations [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. The uptake of cellular contents by such transfers may be via exosomes, tunnelling nanotubes, or a mechanism we recently reported and termed ‘cell-projection pumping’ and these can significantly change the phenotype of acceptor cells [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

“…Cell-projection pumping is a hydrodynamic mechanism, whereby retracting cell-projections inject their cytoplasmic contents into adjacent cells [ 3 ]. A recent independent report supports the novel cell-projection pumping mechanism and relates chemotherapy resistance of multiple myeloma cells to the uptake of mitochondria from co-cultured bone marrow-derived stromal cells [ 21 ].…”

“…The uptake of cellular contents by such transfers may be via exosomes, tunnelling nanotubes, or a mechanism we recently reported and termed ‘cell-projection pumping’ and these can significantly change the phenotype of acceptor cells [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. The transfer of mitochondria appears especially significant and can confer chemotherapy resistance to cancer cells [ 4 , 6 , 7 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. However, we are made wary of ascribing most phenotypic effects to mitochondrial exchange by our observation that, in addition to mitochondria, there is also bulk transfer of cytoplasmic proteins, plasma membrane-bound alkaline phosphatase and organelles smaller than mitochondria [ 1 , 2 , 3 ].…”

Metabolic Disorders in Multiple Myeloma

“…Preclinical studies have shown that anti-myeloma drugs exert a selective pressure on myeloma cells, which have increased energy demands for survival. Myeloma cells can hijack mitochondria from nearby bone marrow mesenchymal stem cells through partial cell fusion and tunneling nanotubes [ 148 ]. Therefore, myeloma cells acquire resistance to chemotherapeutic drugs.…”

Myeloma: A Lot of Progress, Still a Long Way to Go

“…Recently, it has become well accepted that individual cells may no longer be considered the fundamental units of cell biology. In a publication by Matula and co-workers [ 2 ], evidence is provided about the role of mitochondrial exchange between myeloma cells and their neighbouring stromal cells. From co-culture studies, data have emerged that show myeloma cells rapidly respond to the presence of anti-myeloma drugs by acquiring mitochondria from non-malignant stromal cells and delivering “damaged” mitochondria in exchange.…”