Clarke Harrison A, Hawkinson Tara R, Shedlock Cameron J, Medina Terrymar, Ribas Roberto A, Wu Lei, Liu Zizhen, Ma Xin, Xia Yi, Huang Yu, He Xing, Chang Josephine E, Young Lyndsay E A, Juras Jelena A, Buoncristiani Michael D, James Alexis N, Rushin Anna, Merritt Matthew E, Mestas Annette, Lamb Jessica F, Manauis Elena C, Austin Grant L, Chen Li, Singh Pankaj K, Bian Jiang, Vander Kooi Craig W, Evers B Mark, Brainson Christine F, Allison Derek B, Gentry Matthew S, Sun Ramon C
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA.
Nat Metab. 2025 Mar 11. doi: 10.1038/s42255-025-01243-8.
Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.
肺腺癌（LUAD）是一种由致癌驱动因素和代谢重编程所定义的侵袭性癌症。在此，我们利用下一代空间筛选技术，将糖原鉴定为一种关键且此前未被充分探索的致癌代谢物。对人类LUAD样本进行的高通量空间分析显示，糖原积累与肿瘤分级增加及生存率低相关。此外，我们通过饮食干预或基因模型评估了糖原水平升高对LUAD的影响。提高糖原水平的方法提供了令人信服的证据，表明糖原水平升高会显著加速肿瘤进展，促使形成更高分级的肿瘤，而糖原合酶的基因敲除则有效抑制了肿瘤生长。为了进一步建立糖原与细胞代谢之间的联系，我们开发了一种多重空间技术，以同时评估糖原和细胞代谢物，揭示了糖原水平与肿瘤生长所必需的中心碳代谢物升高之间的直接关系。我们的研究结果支持糖原积累驱动LUAD癌症进展这一结论，并提供了一个将空间代谢组学与转化模型相结合以揭示癌症代谢驱动因素的框架。
