Description and purpose
In multiple myeloma (MM), a bone marrow malignancy, osteolytic lesions severely impact patients’ quality of life. Bone lesions are associated with changes in bone marrow glutamine levels, due to excessive consumption by MM cells. The unique metabolic environment hinders the osteoblastic differentiation of mesenchymal stromal cells (MSCs), thus promoting bone lesions. The mechanisms underlying the effect are still unknown.
Purpose
The project aims to understand the mechanisms by which the decrease of bone marrow glutamine, caused by myeloma cell proliferation and metabolism, inhibits the osteoblastic differentiation of MSCs. Specifically, EROSION aims to identify and characterize the signaling and metabolic pathways involved in the inhibition of osteoblastic differentiation and impairment of bone formation.
Expected results
The project goal was to better understand the metabolic interactions between MM cells and the other bone marrow cell populations, identifying the mechanisms underlying the inhibition of osteogenesis and the metabolites involved. The success of the project will lay the bases for innovative metabolic and nutritional therapeutic approaches able to inhibit tumor growth and to prevent osteolytic lesions.
Achieved results
In MSCs, glutamine deficiency causes oxidative and nutritional stress, alters β-catenin activity, and induces Glutamine Synthetase (GS), favoring the formation of adipocytes instead of osteoblasts. Asparagine, a glutamine metabolite, is reduced and, when supplemented, corrects the differentiation defect (manuscript in preparation). Moreover, through glutamine synthesis and secretion, MSCs promote the growth of MM cells, an effect blocked by GS inhibition (publication under review).
