Fig. 4

Overview of the metabolic interactions between MM cells and other components of the BM environment. MM cells are able to influence metabolism of neighboring cell types in the BM microenvironment and vice-versa. BMSC transfer their mitochondria to MM cells through tunnelling nanotubes, increasing ATP values and decreasing superoxide concentrations. Moreover, BMSC-derived exosomes contain high levels of lactic acid and glutamic acid, which is hypothesized to affect MM cell metabolism. MM cells also stimulate stromal cells to increase their glutamine production by upregulation of glutamine synthetase. MM cells release several factors, including TGF-β, EMMPRIN and miR-214, miR-31 and miR-155, stimulating CAFs to increase their glutamine production and secretion of lactate, pyruvate and other amino acids. Known as the Reverse Warburg effect, these metabolites are then taken up again by the MM cells, stimulating oxidative phosphorylation in the MM cells. T-lymphocytes of RRMM patients also show metabolic alterations, including an increase in mitochondrial mass and β-oxidation. Preadipocytes show an increase in glycolysis, oxidative phosphorylation and decrease in adipogenesis, induced by the neighboring MM cells. Moreover, MM cells stimulate adipocytes to produce and release fatty acids, which in turn is used by the MM cells as nutrients. MM cells will also upregulate their fatty acid transporters. The hypoxic BM environment greatly influences MM metabolism by upregulating glycolysis, autophagy and proline metabolism. Reduced levels of oxidative phosphorylation were also observed. Finally, ECM-protein Reelin increases glycolysis in MM cells. ECM: extracellular matrix, BMSC: bone marrow stromal cell, CAF: cancer-associated fibroblast, OX PHOS: oxidative phosphorylation, MM: multiple myeloma, RRMM: relapsed/refractory multiple myeloma, BM: bone marrow. Created with BioRender.com