Abstract
AbstractAdipocytes 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 and smoldering MM, exhibit significant upregulation of adipogenic commitment compared with healthy donors. In vitro coculture assays revealed an adipocyte-induced increase in MM cell proliferation in monoclonal gammopathy of undetermined significance/smoldering MM compared with newly diagnosed MM. Using murine MM cell/BM adipocyte coculture assays, we describe 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 (FFAs) by adjacent MM cells. The effect of FFAs on MM cells was dose dependent and revealed increased proliferation at lower concentrations vs 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 displayed 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.
Highlights
Multiple myeloma (MM) is highly dependent on the tumor microenvironment (TME)
BM stromal cells (BMSCs) from monoclonal gammopathy of undetermined significance (MGUS)/ smoldering MM (SMM) patients showed significantly higher expression of markers of adipogenic commitment: that is, leptin-receptor (LepR), critical for adipogenic commitment[22]; Pref-1, expressed in adipocyte precursors[23]; and Perilipin A associated with lipid droplets[24] (Figure 1A-B)
To evaluate the effect of MM cells on adipocyte differentiation, BMSCs from healthy donors (HD) and patients with MGUS, SMM, and newly diagnosed MM (NDMM) were induced to differentiate into adipocytes in the presence of MM.1S cells, a human MM cell line.[25]
Summary
Multiple myeloma (MM) is highly dependent on the tumor microenvironment (TME). Clonal expansion of plasma cells in bone marrow (BM) is regulated by the BM TME and affects initiation, progression, survival, and evasion from therapies.[1] BM adipocytes (BMAds) comprise 70% of the BM volume in a typical patient with MM, and despite being a significant part of the TME, their specific role in MM pathogenesis and progression remains largely unknown. Cancer-associated adipocytes (CAA) have been shown to support solid tumor progression through: (1) secretion of adipokines; (2) synergistic metabolic reprogramming between cancer cells and CAA; and (3) modulation of TME such as T-cell suppression through overexpression of programmed cell death-ligand 1.2,3 High-proliferative tumor cells have enhanced metabolic demands, triggering alternative metabolic pathways, including glycolysis and fatty acid (FA) oxidation.[4] Adipocytes primarily store and release free FAs (FFAs) to support local and systemic metabolic demands. As with CAA, BMAds have been implicated in support of BM-originating or BM-homing tumors such as metastasizing prostate and breast cancer cells, or acute myeloid leukemia (AML), via the secretion of lipid chaperone FABP4 in BMAds[6,7] or by modulation of cell–cell communication proteins.[8]
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