In situ mass spectrometry imaging reveals heterogeneous glycogen stores in human normal and cancerous tissues

• Published in: EMBO molecular medicine Vol. 14; no. 11; pp. e16029 - n/a
• Main Authors: Young, Lyndsay E A, Conroy, Lindsey R, Clarke, Harrison A, Hawkinson, Tara R, Bolton, Kayli E, Sanders, William C, Chang, Josephine E, Webb, Madison B, Alilain, Warren J, Vander Kooi, Craig W, Drake, Richard R, Andres, Douglas A, Badgett, Tom C, Wagner, Lars M, Allison, Derek B, Sun, Ramon C, Gentry, Matthew S
• Format: Journal Article
• Language: English
• Published: England EMBO Press 08.11.2022; John Wiley and Sons Inc; Springer Nature
• Subjects: Aging; Alzheimer's disease; Animals; Antigens; Architecture; Bone cancer; Bone Neoplasms; Brain architecture; Cancer; Child; Chromatography; Enzymes; Ewing sarcoma; Ewing's sarcoma; Ewings sarcoma; Glucose; Glycogen; glycogen storage disease; Humans; Ions; Kidneys; Lasers; Liver; Localization; MALDI imaging; Male; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolites; Mice; Neuroimaging; Osteosarcoma; Pediatrics; Phosphate esters; Phosphorylation; Physiology; Polymers; Questioning; Sarcoma, Ewing - pathology; Scientific imaging; Spatial distribution; spatial metabolism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods; Tumors; glycogen storage disease; Ewing sarcoma; glycogen; spatial metabolism; MALDI imaging
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202216029

Glycogen dysregulation is a hallmark of aging, and aberrant glycogen drives metabolic reprogramming and pathogenesis in multiple diseases. However, glycogen heterogeneity in healthy and diseased tissues remains largely unknown. Herein, we describe a method to define spatial glycogen architecture in mouse and human tissues using matrix‐assisted laser desorption/ionization mass spectrometry imaging. This assay provides robust and sensitive spatial glycogen quantification and architecture characterization in the brain, liver, kidney, testis, lung, bladder, and even the bone. Armed with this tool, we interrogated glycogen spatial distribution and architecture in different types of human cancers. We demonstrate that glycogen stores and architecture are heterogeneous among diseases. Additionally, we observe unique hyperphosphorylated glycogen accumulation in Ewing sarcoma, a pediatric bone cancer. Using preclinical models, we correct glycogen hyperphosphorylation in Ewing sarcoma through genetic and pharmacological interventions that ablate in vivo tumor growth, demonstrating the clinical therapeutic potential of targeting glycogen in Ewing sarcoma. Synopsis Development of a MALDI‐based assay for the spatial quantification of microenvironmental glycogen and glycogen biochemical architecture. Hyperphosphorylated glycogen was discovered in human Ewing sarcoma. Targeting tumor‐specific glycogen may be a potential therapeutic approach for Ewing sarcoma. Development of a MALDI‐based assay for the spatial quantification of microenvironmental glycogen. Ultra‐sensitivity allows visualization of glycogen in previously unknown but distinct cellular layers in multiple human tissues. Identification of glycogen‐rich and glycogen‐poor tumors such as Ewing sarcoma and prostate cancer, respectively. Targeting Ewing sarcoma glycogen by different modalities blunted tumor growth in immunodeficient mice. Development of a MALDI‐based assay for the spatial quantification of microenvironmental glycogen and glycogen biochemical architecture. Hyperphosphorylated glycogen was discovered in human Ewing sarcoma. Targeting tumor‐specific glycogen may be a potential therapeutic approach for Ewing sarcoma.