Journal of hepatology · 2025
Multiomic analysis uncovers a continuous spectrum of differentiation and Wnt-MDK-driven immune evasion in hepatoblastoma.
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Münter Daniel, de Faria Flavia W, Richter Mathis, Aranda-Pardos Irene, Hotfilder Marc, Walter Carolin, Paga Enya, Inserte Clara, Albert Thomas K, Roy Rajanya, Rahman Shariyah, Riedel Nicole C, Müller Volker, Pascher Andreas, Wiebe Karsten, Schmid Irene, Vokuhl Christian, Winkler Beate, Jüttner Eva, Vieth Simon, Mücke Urs, Kluiver Thomas A, Peng Weng Chuan, Rossig Claudia, Schlué Jerome, Madadi-Sanjani Omid, Sandmann Sarah, Hartmann Wolfgang, A-Gonzalez Noelia, Soehnlein Oliver, Kerl Kornelius
Аннотация
BACKGROUND & AIMS: Hepatoblastoma is the most common pediatric cancer of the liver, with the majority of cases displaying 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-sequencing (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.
IMPACT AND IMPLICATIONS: Despite hepatoblastoma being the most common pediatric liver cancer, there has been a critical knowledge gap in understanding how the tumor microenvironment and immune landscape contribute to disease progression. Our novel findings, revealing a continuous spectrum of tumor differentiation states and Wnt-MDK-driven immune evasion, are significant for pediatric oncology clinicians and researchers, improving our functional understanding of the immune environment of hepatoblastoma. The identification of midkine as a tumor-specific immunomodulator suggests a potential for developing new targeted therapies, though further mechanistic and practical validation would be needed to realize clinical translation of these findings.
METHODS: Single-cell/-nucleus RNA-sequencing (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.
IMPACT AND IMPLICATIONS: Despite hepatoblastoma being the most common pediatric liver cancer, there has been a critical knowledge gap in understanding how the tumor microenvironment and immune landscape contribute to disease progression. Our novel findings, revealing a continuous spectrum of tumor differentiation states and Wnt-MDK-driven immune evasion, are significant for pediatric oncology clinicians and researchers, improving our functional understanding of the immune environment of hepatoblastoma. The identification of midkine as a tumor-specific immunomodulator suggests a potential for developing new targeted therapies, though further mechanistic and practical validation would be needed to realize clinical translation of these findings.