A metabolic trade-off between malignant plasma cells and mesenchymal stromal cells sustains multiple myeloma growth

• MM cells induce glutamate uptake and glutamine production in MSCs. • Targeting glutamate uptake and glutamine synthesis in MSCs limits MM cell growth. Multiple myeloma (MM) is a glutamine-auxotroph and glutamine-addicted cancer, with Glutamine Synthetase (GS) – deficient MM cells avidly taking up extracellular glutamine to sustain their metabolism. Thus, MM cells create a peculiar metabolic niche in the patients’ bone marrow (BM), where low levels of glutamine contribute to the osteolytic bone lesions by inhibiting the osteoblastic differentiation of mesenchymal stromal cells (MSCs). The effects of the altered MM metabolic niche on other BM cell populations remain to be clarified. We demonstrate here that MM cells secrete high amounts of glutamate through the exchange transporter SLC7A11 /xCT. In turn, BM MSCs, but neither MM cells nor osteoblasts, actively take up extracellular glutamate through the transporter EAAT3 ( SLC1A1 ), whose expression decreases during osteogenesis. GS-positive MSCs secrete glutamine, a process boosted by extracellular glutamate in undifferentiated MSCs, but not in differentiated osteoblasts. Co-culture of MSCs with MM cells promotes the expression of the bidirectional transporter SNAT5 ( SLC38A5 ), suggesting its involvement in glutamine efflux. Consistently, MSCs, derived from either MM patients or healthy donors, sustain MM growth in a low-glutamine environment, an effect suppressed by the inhibition or silencing of glutamate uptake or glutamine synthesis. In conclusion, a metabolic cycle occurs in MM bone marrow microenvironment, where glutamine-auxotroph MM cells extrude glutamate that is converted into glutamine by MSC, sustaining in turn MM anabolism through glutamine secretion. The inhibition of this metabolic trade-off impairs MM cell growth, thus highlighting novel potential, niche-oriented therapeutic targets.