{
  "abstract": "Background Hepatocellular carcinoma (HCC) is a rare tumour in children, but has limited treatment options and typically requires liver transplantation. In adults, immunotherapy is a promising treatment for HCC but there is limited understanding of paediatric HCC microenvironment to know which pathways to target. In addition, certain genetic conditions have a predisposition towards HCC in children, including BSEP deficiency, which is caused by biallelic mutations in ABCB11. We hypothesised that the fibro-inflammation associated with BSEP deficiency contributes to development of HCC through a tumour-promoting microenvironment.Methods We performed VisiumHD on two samples of liver explants from patients with BSEP deficiency and HCC, plus control liver tissue (histologically normal, unaffected tissue adjacent to hepatoblastoma resections). VisiumHD is a cutting-edge spatial transcriptomics technology that profiles ~15,000 genes in up to 8µm regions. We utilised standard Seurat pipelines for data analysis. Candidate targets were validated with mulitplex immunohistochemistry.Results Unbiased clustering demonstrated separation of HCC from background liver parenchyma (figure 1A and D). Both tumours were GPC3 positive (figure 1B). Comparing HCC and hepatocytes clusters using differential gene expression, we found 112 down-regulated and 153 up-regulated genes that were consistent across both patients. Down-regulated genes included many fundamental metabolic enzymes, including ALDOB, HPD, ARG1, and OTC. The top upregulated gene pathway was ‘Regulation of DNA-templated Transcription (GO:0006355)’ due to increased expression of genes promoting transcription (e.g. HDAC10). Genes related to B-cell activity (e.g. immunoglobulin heavy chains - IGHG3, figure 1C) were strongly expressed in clusters in the peri-tumour tissue but excluded from the tumour tissue. Whereas tumour associated macrophages (CD163+ CD5L+) were increased in HCC.Conclusions HCC arising on the background of BSEP deficiency is associated with profound metabolic perturbation. The peri-tumour fibroinflammation is rich in B-cells, whilst the tumour is infiltrated with macrophages typically associated with cancer progression. Further mechanistic work is required to understand how these interact to lead to tumour development.Abstract OC35 Figure 1Spatial transcriptomics of hepatocellular carcinoma (HCC) in BSEP deficiency liverexplants. A: overview of explant A, showing the region captured by VisiumHD, with colours representingdifferent clusters. Spatial distribution of expression of GPC3 (B) and IGHG3 (C) in explant A. D: overview of explant B, showing different clusters across tumour (blue and dark blue), background cirrhotic nodules (yellow) and fibrotic regions (red). E: expression of ABCB4 in explant B",
  "authors": [
    {
      "affiliations": [
        "University of Birmingham"
      ],
      "name": "Annabelle Schofield"
    },
    {
      "affiliations": [
        "University of Birmingham"
      ],
      "name": "Rebecca Jeyaraj"
    },
    {
      "affiliations": [
        "Liver Unit (including small bowel transplantation), Birmingham Children’s Hospital"
      ],
      "name": "Alba Bueno-Jimenez"
    },
    {
      "affiliations": [
        "Liver Unit (including small bowel transplantation), Birmingham Children’s Hospital"
      ],
      "name": "Khalid Sharif"
    },
    {
      "affiliations": [
        "Liver Unit (including small bowel transplantation), Birmingham Children’s Hospital",
        "Liver unit, Queen Elizabeth Hospital Birmingham"
      ],
      "name": "Rebeca Mateos"
    },
    {
      "affiliations": [
        "Liver Unit (including small bowel transplantation), Birmingham Children’s Hospital"
      ],
      "name": "Hector Vilca-Melendez"
    },
    {
      "affiliations": [
        "University of Birmingham",
        "Liver Unit (including small bowel transplantation), Birmingham Children’s Hospital"
      ],
      "name": "Jake Mann"
    }
  ],
  "title": "OC35 Spatial transcriptomics identifies mechanisms of hepatocellular carcinoma development in BSEP deficiency",
  "uid": "ffb370c5-f2ae-5667-bc34-33b78aa03f13"
}