脂解
脂毒性
不确定意义的单克隆抗体病
脂肪细胞
脂肪组织
下调和上调
内分泌学
内科学
化学
脂肪酸
生物化学
生物
癌症研究
单克隆
医学
免疫学
单克隆抗体
抗体
胰岛素抵抗
基因
胰岛素
作者
Cristina Panaroni,Keertik Fulzele,Tomoaki Mori,Ka Tat Siu,Chukwuamaka Onyewadume,Allison Maebius,Noopur Raje
出处
期刊:Blood
[American Society of Hematology]
日期:2021-10-20
卷期号:139 (6): 876-888
被引量:62
标识
DOI:10.1182/blood.2021013832
摘要
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 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.
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