Increased lipolysis was further associated with increased FA synthesis (increased LPL, ACSL1, and ACSL4) (Figure 2F) and increased FA desaturation (SCD1 and FASD2) (Figure 2G). SGC-CBP30 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 cellCinduced lipolysis in BM adipocytes and suggest prevention of FFA uptake by MM cells as a potential target for myeloma therapeutics. Introduction 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 SGC-CBP30 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. CAA provide a metabolic niche for malignant cells via FFAs. Studies have shown that gonadal fat provides FFAs to leukemia stem cells and protects them from chemotherapy.5 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 BMAds6,7 or SGC-CBP30 by modulation of cellCcell communication proteins.8 In patients with MM, obesity-induced increases in BMAd numbers and volume are associated with an increased risk of developing myeloma.9-11 Nearly one-third of patients with monoclonal gammopathy of undetermined significance (MGUS) and MM have lipid-reactive clonal immunoglobulins,12 and obese patients with MGUS are 20% more likely to progress to MM.13 Obesity-induced deregulation of lipids14 and diet-induced obesity were found to promote a myeloma-like syndrome in mice.15 In addition, mature adipocytes confer drug resistance by protecting MM cells from chemotherapy by secretion of adipokines and activation of autophagy.16 Conversely, MM cells also reprogram BMAds (eg, by expressing factors supporting osteoclastogenesis and suppressing osteoblastogenesis, leading to increased bone lesions).17 The complex mechanisms involved in Rabbit polyclonal to LPA receptor 1 BMAd and MM cell interaction are a topic of intense investigation. In vitro cocultures have shown that pre-adipocytes promote chemotaxis in MM cells by activating Wnt signaling, whereas mature adipocytes promote MM SGC-CBP30 cell proliferation by activating ERK signaling.18 In vivo studies showed that MM cells facilitate their progression by decreasing the secretion of tumor-suppressing adiponectin from BMAds.19 Here we use patient-derived cells and in?vitro and in?vivo models to show that MM cells induce lipolysis in BMAds and that the released FFAs are then taken up by MM cells through FA transporter proteins (FATPs). SGC-CBP30 Inhibition of either BMAd lipolysis or FFA transporter into MM cells could be a potential novel strategy to prevent MM progression. Materials and methods Isolation of.
