Abstract 4709: Spatial whole transcriptome profiling of human normal liver and HCC uncovers unique insights into metabolic zonation

Abstract Understanding the physiology and functions of the liver and cancer requires knowing transcriptional patterns driving biological activities within the functional structures of the tissue, especially the zonated features of the liver metabolic networks. Using the powerful and unique capabilities of GeoMx® Digital Spatial Profiler (DSP) with the Whole Transcriptome Atlas (WTA) panel to resolve functional units within FFPE tissues in situ, here we report the spatial analysis of whole transcriptomes across three micro-dissected zones (pericentral zone 3, intermediate zone 2 and periportal zone 1) of human normal liver and HCC. We also report the whole transcriptome expression data from Kupffer cells, portal traits and interlobular bile ducts from four normal liver samples and HCC. 500 - 3000 genes were detected from functional groups within each histological structure. In the liver functional units, 1000 - 2500 genes were detected in zone 1, 2 and 3 separately. By comparing the whole transcriptome profiles of zone 1 and zone 3, we have found 32 differentially expressed targets (fold change > 1.5, p value < 0.05) which showed a gradient expression pattern along the porto-central axis. The expression patterns of CYP1A2, CYP2E1, CYP3A4 and ALDOB matched well with their respective patterns of protein expression (Human Protein Atlas), recapitulating the well-studied distribution of functional activities along the porto-central axis. Moreover, by combining with Gene Set Enrichment Analysis (GSEA), we have found important pathways involved in metabolisms in either the pericentral area or the periportal area. Pathways including biological oxidations (CYP1A2, CYP2E1, CYP3A4, ADH1A, and ADH1B) and lipids metabolism (AKR1C1, AKR1C2, and SLCO1B3) showed high enrichment in zone 3 and decreased towards zone 1. In contrast, pathways including platelet degranulation (FGA, FGB, FGG), glucose metabolism (ALDOB and PCK1) and amino acids metabolism (HAL, SDS, NNMT, and GLS2) showed high enrichment in zone 1 and decreased towards zone 3. In conclusion, our WTA data has revealed clear metabolic zonation in the liver along the porto-central axis. GeoMx technology with WTA is a powerful tool to investigate the underlying mechanisms of liver metabolism, regeneration, and tissue structure. It can be further utilized to study the whole transcriptomic differences in normal and diseased tissue. FOR RESEARCH USE ONLY. Not for use in diagnostic procedures. Citation Format: Yan Liang, Nan Wang, Xia Li, Kathy Ton, Liang Zhang, Megan Vandenberg, Charlie Glaser, Zhiyong Ding, Joseph Beechem, Andy Nam, Yan Liang. Spatial whole transcriptome profiling of human normal liver and HCC uncovers unique insights into metabolic zonation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4709.