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| Status |
Public on Feb 07, 2025 |
| Title |
Multiomic analysis uncovers a continuous spectrum of differentiation and Wnt-MDK-driven immune evasion in hepatoblastoma [snRNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background & Aims: Hepatoblastoma is the most common pediatric cancer of the liver and the majority of cases display activating mutations in the Wnt/β-catenin pathway. Understanding the complex milieu of the tumor microenvironment has resulted in promising new therapies for adult cancers, but similar approaches in pediatric cancers are still lacking. We aimed to provide a comprehensive analysis of the tumor microenvironment of hepatoblastoma unveiling its spatial architecture and key signaling mechanisms.
Methods: Single-cell/-nucleus RNA-seq (n=15), spatial transcriptomics (n=22), and multiplex immunofluorescence stainings (n=7) of treated, untreated, and metastasized pediatric hepatoblastomas were performed. An RNA-seq validation cohort (n=110) including hepatoblastoma, non-tumor and fetal liver samples and single-cell RNA-seq data of healthy immune cells were used for further analysis. Western blotting and RNA-seq of hepatoblastoma and macrophage cell lines were conducted for experimental validation.
Results: Of four identified transcriptional tumor programs, “Developmental” and “Metabolic” reflected different hepatic differentiation stages, while “Cycling” was enriched in undifferentiated cells and relapsed samples, and “Intermediate” displayed high activity in samples from patients with poor outcomes. We discovered an increased ratio of anti- to pro-inflammatory immune cells and evidence of immune exclusion from tumor areas. Wnt-responsive upregulation of the immunomodulator midkine in hepatoblastoma cells was associated with a change in macrophage phenotype, which could be partially reversed through midkine inhibition.
Conclusions: Hepatoblastoma cells exist along a continuous spectrum of hepatic differentiation and inhabit an altered immune environment. Wnt signaling augments midkine expression, which appears to be involved in shaping the immune environment by modifying macrophages to enable immune evasion, thereby providing a potential therapeutic target.
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| Overall design |
Single-nuclei gene expression profiles of human hepatoblastoma were generated from formalin-fixed, paraffin-embedded tissue samples (n=5) using Chromium Single Cell Flex Gene Expression (10x Genomics).
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| Contributor(s) |
Münter D, de Faria FW, Richter M, Aranda-Pardos I, Hotfilder M, Walter C, Paga E, Inserte C, Albert TK, Roy R, Rahman S, Riedel NC, Müller V, Pascher A, Wiebe K, Schmid I, Vokuhl C, Winkler B, Jüttner E, Vieth S, Mücke U, Kluiver TA, Chuan Peng W, Rossig C, Schlué J, Madadi-Sanjani O, Sandmann S, Hartmann W, A-Gonzalez N, Soehnlein O, Kerl K |
| Citation(s) |
- Münter D, de Faria FW, Richter M, Aranda-Pardos I et al. Multiomic analysis uncovers a continuous spectrum of differentiation and Wnt-MDK-driven immune evasion in hepatoblastoma. J Hepatol 2025 Feb 1. PMID: 39900120
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| Submission date |
Nov 29, 2024 |
| Last update date |
Feb 08, 2025 |
| Contact name |
Kornelius Kerl |
| Organization name |
University Children's Hospital Münster
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| Department |
Department of Pediatric Hematology and Oncology
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| Street address |
Albert-Schweitzer-Campus 1
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| City |
Münster |
| ZIP/Postal code |
48149 |
| Country |
Germany |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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