Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, 77030, USA.
Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Nat Commun. 2022 Jun 28;13(1):3728. doi: 10.1038/s41467-022-31331-2.
Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.
神经母细胞瘤（NB）是一种起源于交感肾上腺神经嵴细胞的儿童癌症。MYCN 扩增存在于一半的高危 NB 患者中；然而，目前没有可直接针对 MYCN 的治疗方法。我们使用 MYCN 表达系统和原发性患者肿瘤的多维代谢谱分析，全面描述了 MYCN 在 NB 中驱动的代谢特征。MYCN 扩增通过促进脂肪酸（FA）摄取和生物合成导致甘油磷脂积累。我们发现表达扩增型 MYCN 的细胞高度依赖 FA 摄取来维持生存。在机制上，MYCN 直接上调脂肪酸转运蛋白 2（FATP2），由 SLC27A2 编码。SLC27A2 的基因缺失会损害 NB 的生存能力，而药理学上抑制 SLC27A2 选择性地抑制肿瘤生长，延长动物生存时间，并在多种临床前 NB 模型中与常规化疗联合使用时发挥协同抗肿瘤作用。这项研究确定了 FA 摄取是 MYCN 扩增肿瘤的关键代谢依赖性。抑制 FA 摄取是改善当前治疗方案的有效方法。
