Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cancer Cell. 2023 Jun 12;41(6):1048-1060.e9. doi: 10.1016/j.ccell.2023.05.001. Epub 2023 May 25.
Malignant tumors exhibit heterogeneous metabolic reprogramming, hindering the identification of translatable vulnerabilities for metabolism-targeted therapy. How molecular alterations in tumors promote metabolic diversity and distinct targetable dependencies remains poorly defined. Here we create a resource consisting of lipidomic, transcriptomic, and genomic data from 156 molecularly diverse glioblastoma (GBM) tumors and derivative models. Through integrated analysis of the GBM lipidome with molecular datasets, we identify CDKN2A deletion remodels the GBM lipidome, notably redistributing oxidizable polyunsaturated fatty acids into distinct lipid compartments. Consequently, CDKN2A-deleted GBMs display higher lipid peroxidation, selectively priming tumors for ferroptosis. Together, this study presents a molecular and lipidomic resource of clinical and preclinical GBM specimens, which we leverage to detect a therapeutically exploitable link between a recurring molecular lesion and altered lipid metabolism in GBM.
恶性肿瘤表现出异质性的代谢重编程，这阻碍了针对代谢靶向治疗的可转化弱点的识别。肿瘤中分子改变如何促进代谢多样性和不同的可靶向依赖性仍然定义不明确。在这里，我们创建了一个由 156 个分子多样化的胶质母细胞瘤（GBM）肿瘤和衍生模型的脂质组学、转录组学和基因组学数据组成的资源。通过将 GBM 脂质组与分子数据集进行综合分析，我们发现 CDKN2A 缺失重塑了 GBM 的脂质组，特别是将可氧化的多不饱和脂肪酸重新分配到不同的脂质隔室中。因此，CDKN2A 缺失的 GBM 显示出更高的脂质过氧化，选择性地为铁死亡启动肿瘤。总之，这项研究提供了一个临床和临床前 GBM 标本的分子和脂质组学资源，我们利用这个资源来检测在 GBM 中反复出现的分子病变和改变的脂质代谢之间的治疗可利用的联系。
