Spatial Glyco-Codes Define Human Liver Pathology and Progression
Abstract
Glycosylation is a fundamental process regulating cellular function, tissue organization, and disease progression. However, comprehensive glycan profiling at single-cell spatial resolution remains largely inaccessible, particularly in clinical archival tissues. Here we develop spatial-GPT, a multimodal platform for simultaneous profiling of glycans, proteins, and/or transcripts in archival formalin-fixed paraffin-embedded (FFPE) tissues. Using a panel of 30 DNA-encoded lectins recognizing major mammalian glycan motifs and structural classes, sequencing-based spatial-GPT (DBiT-GPT) mapped the spatial glycome, proteome, and transcriptome across 16 human liver specimens encompassing steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), leading to identification of spatial glyco-codes - combinatorial glycan states associated with distinct cellular identities, tissue features, and pathological processes. Unexpectedly, glyco-codes alone were sufficient to resolve major cell types, disease states, and HCC subtypes, revealing a previously unappreciated level of biological information encoded within the tissue glycome. Spatial glycomics uncovered tumor-like glyco-codes in premalignant regions, suggesting that glycan reprogramming may precede overt malignant transformation. Using imaging-based single-cell spatial glycan-protein profiling (CODEX-GP), we track glyco-codes across the whole-tissue architecture of 3 representative HCC samples. We further examined the…
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