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Human cerebellar organoids to study medulloblastoma pathogenesis and treatment. [scRNA-Seq]

ABSTRACT: Faithful in vivo models of Group 4 medulloblastoma (G4 MB) are currently unavailable and recent studies showed the unique role of human-specific progenitors in the development of G3 and G4 MB. Here, we obtained cerebellar organoid (CbO) from expanded potential stem cells (EPSC) and developed them in vitro as 3D structures. We performed extensive characterisation of the epigenetic and transcriptomic profile of the mature CbO confirming the presence of sub compartment-specific cerebellar lineages linked to MB formation, including populations expressing signature genes reminiscent of the G3 and G4 MB cell-of-origin never described before. In parallel we have established a protocol to co-culture primary MB cells with our CbO to generate CbO-MB models. We confirmed that CbO sustains MB cells proliferation and invasion while preserving their molecular identity, and that CbO-MB recapitulated the efficacy of in vivo anti-tumour therapy, hence representing a suitable model to gain insight into G3/G4 MB pathogenesis and to set up pre-clinical drug screening.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263652 | GEO | 2026/04/30

REPOSITORIES: GEO

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Human cerebellar organoids to study medulloblastoma pathogenesis and treatment. [methylation]

Project description:Faithful in vivo models of Group 4 medulloblastoma (G4 MB) are currently unavailable and recent studies showed the unique role of human-specific progenitors in the development of G3 and G4 MB. Here, we obtained cerebellar organoid (CbO) from expanded potential stem cells (EPSC) and developed them in vitro as 3D structures. We performed extensive characterisation of the epigenetic and transcriptomic profile of the mature CbO confirming the presence of sub compartment-specific cerebellar lineages linked to MB formation, including populations expressing signature genes reminiscent of the G3 and G4 MB cell-of-origin never described before. In parallel we have established a protocol to co-culture primary MB cells with our CbO to generate CbO-MB models. We confirmed that CbO sustains MB cells proliferation and invasion while preserving their molecular identity, and that CbO-MB recapitulated the efficacy of in vivo anti-tumour therapy, hence representing a suitable model to gain insight into G3/G4 MB pathogenesis and to set up pre-clinical drug screening. DNAme analysis of cerebellar organoids derived from 2 EPSC lines during development, then comparison of DNAme profiles of cerebellar organoids to human foetal cerebellum during development

2026-04-30 | GSE263653 | GEO

Single cell transcriptional and chromatin accessibility profiling identify the cellular heterogeneity of human medulloblastoma

Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of chromosome occupation and single cell gene expression or single nuclei chromatin accessibility in medulloblastoma tissues or cells. To further define the cellular identity at the single cell level, we characterized 26 MB tissues including 18 newly diagnosed MB tumor tissues by single cell scRNA-seq and scATAC-seq (the assay for transposase-accessible chromatin-sequencing) together with 8 previously reported MB single cell transcriptomics. The newly diagnosed MB tumors included four SHH-MBs (45,731 cells), nine G3-MBs (82,834 cells), thirteen G4 MBs (77,521 cells) with a median of 7,926 cells for scRNA-seq and 9,342 cells for scATAC-seq per MB tumor, respectively. To decipher how dynamic accessibility at the cis-regulatory elements (CREs) relates to the gene regulatory program in TCP-like cells from G3- and G4- MBs, we performed single nuclei ATAC-seq (snATAC-seq) to determine the single-cell chromatin accessibility landscape using high-quality nuclei from a set of fresh G3 and G4 MB tumors that matched with scRNA-seq. Finally, we show that gene expression with chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms. Our studies identified a human-specific intermediate progenitor population important for cerebellar neural lineage development and the growth and metastasis of aggressive MBs, highlighting potential therapeutic targets.

2022-10-08 | GSE198565 | GEO

Primary cilia control translation and the cell cycle in medulloblastoma

Project description:The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis is unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding β-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type–specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, providing new frameworks for studying cilia function in normal and pathologic conditions.

2022-07-04 | GSE207008 | GEO

The MYC-MIZ1 interaction defines tumor identity

Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumor’s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma.

2016-01-21 | GSE64425 | GEO

Proteomics analysis of Medulloblastoma

Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children. It is a neuroectodermal tumor located in the cerebellum. International consensus recognizes four distinct subgroups of MBs including Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3), and Group 4 (G4) with distinct molecular characteristics, prognoses, and mortality rates in patients. Here, we have compiled a large MB cohort encompassing 384 primary MB patient samples with methylome (450k/850k arrays), transcriptome (RNA-seq), proteome, phosphoproteome and metabolome.

2025-12-11 | PXD053458 | Pride

Phosphoproteomics analysis of Medulloblastoma

2025-12-11 | PXD053675 | Pride

Proteomic research on effect of EIF4A1 inhibition in MYC-amplified Group 3 medulloblastoma

Project description:As the most life-threatening subtype of pediatric medulloblastoma (MB), MYC-amplified Group 3 (G3) MB lacks effective and selective therapeutics. We tried to indirectly target MYC (oncogenic driver and cancer-dependent molecule) production via inhibiting translational machinery. Through multiple datasets analyses on components of eIF4F (eukaryotic translation initiation factor 4F) complex, we found that EIF4A1 (major component with RNA helicase activity) has relatively higher expression level and the closest positive correlation with MYC in G3-MB among normal control and other 3 subtypes (e.g., WNT, SHH and G4). Both in vitro and in vivo experiments with MYC-amplified G3-MB cell lines showed effective growth inhibition upon EIF4A1 knockout or inhibitor treatment. Further FACS analysis found decreased cell proliferation and enhanced apoptosis on EIF4A1 inhibitor treatment. To explore the mechanisms of EIF4A1 inhibition on arresting MYC-amplified G3-MB, we performed the whole proteome analyses on corresponding MB cells treated with EIF4A1 inhibitor.

2020-10-15 | PXD022014 |

Musashi-1 is a master regulator of aberrant translation in Group 3 medulloblastoma

Project description:Transcripts bound to Musashi-1 (MSI1) are explored in Group 3 medulloblastoma (G3 MB) and neural stem cells harvested from the cerebellar portion of a embryonal brain

2022-10-28 | GSE126263 | GEO

Myc and N-myc induce distinct medulloblastoma subgroups via Miz1

Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and “reprograms” the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development.

2016-01-21 | GSE66093 | GEO

Identification of lncMB3-dependent transcriptome in MYC-amplified D283 Med cells.

Project description:Medulloblastoma (MB) stands as the most prevalent malignant pediatric tumor affecting the central nervous system. Categorized into four primary subgroups, each with distinct biological and clinical features, MB presents unique therapeutic implications. Group 3 (G3) and 4 (G4) MBs collectively account for the majority of cases (60%) and exhibit the highest degree of aggressiveness. However, these subgroups remain poorly characterized from a biochemical perspective. Therefore, it is crucial to unveil the fundamental molecular mechanisms underlying G3 e G4 MBs to deepen our overall comprehension of these specific conditions and to pave the way for precision medicine-driven approaches. Compared to normal human cerebella, the MYC-dependent lncRNA MB3 was found to be induced in G3-derived cell lines expressing the proto-oncogene and upregulated in G3-MB primary tumors. Consistently, LncMB3 is downregulated upon MYC inhibition and in vitro studies reveal its potent anti-apoptotic activity. To dissect the molecular network through which LncMB3 operates in MB carcinogenesis, we initiated the identification of its target genes by analyzing through RNA-Sequencing the alteration of the transcriptome following LncMB3 knockdown in G3 MB cell lines, achieved through transfections of antisense Locked Nucleic Acid (LNA) oligonucleotides (GapmeRs). Here we provide the data of three polyA+ RNA samples derived from lncMB3 knockdown (KD) and 3 control samples from the MYC-amplified D283 Med cell line that were subjected to RNA-Seq analysis.

2025-09-30 | GSE277976 | GEO

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