Tucci JChen TMargulis KOrgel EPaszkiewicz R.LCohen M.DOberley M.JWahhab RJones A.EDivakaruni A.SCHENG-CHIH HSUNoll S.ESheng XZare R.NMittelman S.D.2022-04-252022-04-2520212234943Xhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85105447139&doi=10.3389%2ffonc.2021.665763&partnerID=40&md5=e9a6042c2c0dfd583a26e533c182a68dhttps://scholars.lib.ntu.edu.tw/handle/123456789/606863Background: There is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells. Methods: We cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes. Results: Adipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells. Conclusion: These findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome. ? Copyright ? 2021 Tucci, Chen, Margulis, Orgel, Paszkiewicz, Cohen, Oberley, Wahhab, Jones, Divakaruni, Hsu, Noll, Sheng, Zare and Mittelman.adipocytesFFAleukemialipid dropletsmicroenvironmentacetyl coenzyme A carboxylasecarboxylyasecitrinincytochrome cdaunorubicindexamethasoneetomoxirfat dropletfatty acid synthasefenofibrategentamicinglucose transporter 4glycerolinterleukin 12interleukin 16interleukin 6interleukin 7ketaminelactic acidmacrophage inflammatory protein 1alphamonocyte chemotactic protein 1monounsaturated fatty acidoleic acidpalmitic acidperoxisome proliferator activated receptor gammaphospholipidRANTESsterol regulatory element binding protein 1ctetrahydrolipstatintriacylglycerolunsaturated fatty acidvincristine3T3-L1 cell lineacute lymphoblastic leukemiaadipocyteadipose tissueadolescentadultanimal cellanimal tissueArticlebioenergybone marrow biopsybreathing ratecancer chemotherapycancer resistancecardiac muscle cellcell killingcell metabolismcell proliferationcell survivalchemotherapychildclinical trial (topic)cocultureconfocal microscopycontrolled studycytokine releasecytotoxicityEC50endoplasmic reticulum stressfatty acid oxidationflow cytometrygene expressionglucose transportglycolysishumanhuman cellhuman tissueIC50immunoblottingimmunofluorescenceimmunofluorescence assayinflammationlipid metabolismlipidomicslipogenesislipolysismacromoleculemalemass spectrometrymitochondrial respirationmousenonhumannuclear reprogrammingobesityoxidative phosphorylationpentose phosphate cycleprotein expressionprotein phosphorylationrespirometryteratomatreadmill exercisetreatment failureyoung adult[SDGs]SDG3[SDGs]SDG14journal article10.3389/fonc.2021.6657632-s2.0-85105447139