Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma
(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect the β-catenin and Wnt pathways; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics...
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2025-01-01
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| Series: | Current Oncology |
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| author | Christophe Desterke Yuanji Fu Jenny Bonifacio-Mundaca Claudia Monge Pascal Pineau Jorge Mata-Garrido Raquel Francés |
| author_facet | Christophe Desterke Yuanji Fu Jenny Bonifacio-Mundaca Claudia Monge Pascal Pineau Jorge Mata-Garrido Raquel Francés |
| author_sort | Christophe Desterke |
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| description | (1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect the β-catenin and Wnt pathways; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: The cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types. In medulloblastoma, LEF1 upregulation is associated with the WNT-subtype. The analysis of LEF1 genome binding occupancy in H1 embryonic stem cells identified 141 LEF1 proximal targets activated in WNT medulloblastoma, 13 of which are involved in Wnt pathway regulation: <i>RNF43</i>, <i>LEF1</i>, <i>NKD1</i>, <i>AXIN2</i>, <i>DKK4</i>, <i>DKK1</i>, <i>LGR6</i>, <i>FGFR2</i>, <i>NXN</i>, <i>TCF7L1</i>, <i>STK3</i>, <i>YAP1</i>, and <i>NFATC4</i>. The ROC curve analysis of the combined expression of these 13 WNT-related LEF1 targets yielded an area under the curve (AUC) of 1.00, indicating 100% specificity and sensitivity for predicting the WNT subtype in the PBTA medulloblastoma cohort. An expression score based on these 13 WNT-LEF1 targets accurately predicted the WNT subtype in two independent medulloblastoma transcriptome cohorts. At the single-cell level, the WNT-LEF1 expression score was exclusively positive in WNT-medulloblastoma tumor cells. This WNT-LEF1-dependent signature was also confirmed as activated in the hepatoblastoma tumor transcriptome. At the single-cell level, the WNT-LEF1 expression score was higher in tumor cells from both human hepatoblastoma samples and a hepatoblastoma patient-derived xenotransplant model; (4) Discussion: This study uncovered a shared transcriptional activation of a LEF1-dependent embryonic program, which orchestrates the regulation of the Wnt signaling pathway in tumor cells from both hepatoblastoma and medulloblastoma. |
| format | Article |
| id | doaj-art-bbb62289478e455fb12f4dc06dc348dd |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| series | Current Oncology |
| spelling | doaj-art-bbb62289478e455fb12f4dc06dc348dd2025-01-24T13:28:26ZengMDPI AGCurrent Oncology1198-00521718-77292025-01-013213510.3390/curroncol32010035Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and MedulloblastomaChristophe Desterke0Yuanji Fu1Jenny Bonifacio-Mundaca2Claudia Monge3Pascal Pineau4Jorge Mata-Garrido5Raquel Francés6Faculté de Médecine du Kremlin Bicêtre, Université Paris-Saclay, INSERM UMRS-1310, 94805 Villejuif, FranceInstitut Necker Enfants Malades, INSERM, CNRS, Université Paris Cité, 75015 Paris, FranceNational Tumor Bank, Department of Pathology, National Institute of Neoplastic Diseases, Lima 15024, PeruInstitut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, 75015 Paris, FranceInstitut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, 75015 Paris, FranceInstitut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, 75015 Paris, FranceEnergy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, 75006 Paris, France(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect the β-catenin and Wnt pathways; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: The cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types. In medulloblastoma, LEF1 upregulation is associated with the WNT-subtype. The analysis of LEF1 genome binding occupancy in H1 embryonic stem cells identified 141 LEF1 proximal targets activated in WNT medulloblastoma, 13 of which are involved in Wnt pathway regulation: <i>RNF43</i>, <i>LEF1</i>, <i>NKD1</i>, <i>AXIN2</i>, <i>DKK4</i>, <i>DKK1</i>, <i>LGR6</i>, <i>FGFR2</i>, <i>NXN</i>, <i>TCF7L1</i>, <i>STK3</i>, <i>YAP1</i>, and <i>NFATC4</i>. The ROC curve analysis of the combined expression of these 13 WNT-related LEF1 targets yielded an area under the curve (AUC) of 1.00, indicating 100% specificity and sensitivity for predicting the WNT subtype in the PBTA medulloblastoma cohort. An expression score based on these 13 WNT-LEF1 targets accurately predicted the WNT subtype in two independent medulloblastoma transcriptome cohorts. At the single-cell level, the WNT-LEF1 expression score was exclusively positive in WNT-medulloblastoma tumor cells. This WNT-LEF1-dependent signature was also confirmed as activated in the hepatoblastoma tumor transcriptome. At the single-cell level, the WNT-LEF1 expression score was higher in tumor cells from both human hepatoblastoma samples and a hepatoblastoma patient-derived xenotransplant model; (4) Discussion: This study uncovered a shared transcriptional activation of a LEF1-dependent embryonic program, which orchestrates the regulation of the Wnt signaling pathway in tumor cells from both hepatoblastoma and medulloblastoma.https://www.mdpi.com/1718-7729/32/1/35LEF1WNTpluripotencypediatric cancerhepatoblastomamedulloblastoma |
| spellingShingle | Christophe Desterke Yuanji Fu Jenny Bonifacio-Mundaca Claudia Monge Pascal Pineau Jorge Mata-Garrido Raquel Francés Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma Current Oncology LEF1 WNT pluripotency pediatric cancer hepatoblastoma medulloblastoma |
| title | Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma |
| title_full | Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma |
| title_fullStr | Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma |
| title_full_unstemmed | Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma |
| title_short | Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma |
| title_sort | single cell rna sequencing reveals lef1 driven wnt pathway activation as a shared oncogenic program in hepatoblastoma and medulloblastoma |
| topic | LEF1 WNT pluripotency pediatric cancer hepatoblastoma medulloblastoma |
| url | https://www.mdpi.com/1718-7729/32/1/35 |
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