Multiple myeloma cells induce lipolysis in adipocytes and uptake fatty acids through fatty acid transporter proteins

Abstract

Adipocytes occupy 70% of the cellular volume within the bone marrow (BM), wherein multiple myeloma (MM) originates and resides. However, the nature of the interaction between MM cells and adipocytes remains unclear. Cancer-associated adipocytes support tumor cells through various mechanisms, including metabolic reprogramming of cancer cells. We hypothesized that metabolic interactions mediate the dependence of MM cells on BM adipocytes. Here, we show that BM aspirates from precursor states of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), demonstrate significant upregulation of adipogenic commitment when compared to healthy donors (HD). In-vitro co-culture assays revealed an adipocyte-induced increase in MM cell proliferation in MGUS/SMM compared with newly diagnosed MM (NDMM). Using murine MM cell/ BM adipocyte co-culture assays, we demonstrate MM-induced lipolysis in adipocytes via activation of the lipolysis pathway. Upregulation of fatty acid transporters 1 and 4 on MM cells mediated the uptake of secreted free fatty acids (FFA) by adjacent MM cells. The effect of FFA on MM cells was dose dependant and revealed increased proliferation at lower concentrations versus induction of lipotoxicity at higher concentrations. Lipotoxicity occurred via the ferroptosis pathway. Exogenous treatment with arachidonic acid, a very long chain FFA, in a murine plasmacytoma model showed a reduction in tumor burden. Taken together, our data reveal a novel pathway involving MM cell-induced lipolysis in BM adipocytes and suggest prevention of FFA uptake by MM cells as a potential target for myeloma therapeutics.