Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Division of Cell Biology, Metabolism & Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Nat Commun. 2022 Sep 13;13(1):5371. doi: 10.1038/s41467-022-33138-7.
The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma.
脂肪酸（FA）代谢在癌症中的重要性已得到充分证实，但代谢重编程的机制仍难以捉摸。在这里，我们确定了四跨膜蛋白 CD37，它是侵袭性 B 细胞淋巴瘤的预后标志物，是 FA 代谢必需的膜定位抑制剂。淋巴瘤细胞中 CD37 的缺失导致功能测定和代谢组学显示 FA 氧化增加。此外，在小鼠研究中，CD37 阴性淋巴瘤选择性地从血清中耗尽棕榈酸。从机制上讲，CD37 通过分子相互作用抑制 FA 转运蛋白 FATP1。因此，CD37 的缺失诱导外源性棕榈酸摄取和加工为能量和增殖的必需构建块，并抑制 FATP1 逆转这种表型。在患者的 CD37 阴性淋巴瘤组织中观察到大量脂质沉积和细胞内脂滴。此外，肉毒碱棕榈酰转移酶 1A 的抑制显著损害了 CD37 缺陷性淋巴瘤的活力和增殖。总的来说，我们的研究结果表明 CD37 是侵袭性 B 细胞淋巴瘤中 FA 代谢开关的直接守门员。
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