Dissecting Super-enhancer driven Transcriptional Dependencies Reveals Novel Oncogenes and Therapeutic Strategies of Group 3 Subtype Medulloblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE185025 | GEO | 2021/10/04
REPOSITORIES: GEO
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Project description:BackgroundMedulloblastoma is the most common malignant pediatric brain tumor and group 3 subtype medulloblastoma (G3-MB) exhibits the worst prognosis. Super enhancers (SEs) are large clusters of enhancers that play important roles in cancer through transcriptional control of cell identity genes, oncogenes and tumor-dependent genes. Dissecting SE-driven transcriptional dependencies of cancer leads to identification of novel oncogenic mechanisms, therapeutic strategies and targets.MethodsIntegrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB were performed to extract the conserved SE-associated gene signatures and their oncogenic potentials were evaluated by gene expression, tumor-dependency and patient prognosis analyses. SE-associated subtype-specific upregulated tumor-dependent genes, which were revealed as members of SE-driven core transcriptional regulatory network of G3-MB, were then subjected to functional validation and mechanistic investigation. SE-associated therapeutic potential was further explored by genetic or pharmaceutical targeting of SE complex components or SE-associated subtype-specific upregulated tumor-dependent genes individually or in combination, and the underlying therapeutic mechanisms were also examined.ResultsThe identified conserved SE-associated transcripts of G3-MB tissues and cell lines were enriched of subtype-specifically upregulated tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated G3-MB-specific upregulated tumor-dependent genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized TFs (MYC, OTX2 and CRX) and eleven newly identified downstream effector genes (ARL4D, AUTS2, BMF, IGF2BP3, KIF21B, KLHL29, LRP8, MARS1, PSMB5, SDK2 and SSBP3). An OTX2-SE-ARL4D regulatory axis was further revealed to represent a subtype-specific tumor dependency and therapeutic target of G3-MB via contributing to maintaining cell cycle progression and inhibiting neural differentiation of tumor cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector gene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB via stronger suppression of SE-associated transcription or higher induction of ER stress, respectively.ConclusionsOur study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic strategies and targets.
| S-EPMC9587669 | biostudies-literature
Project description:Medulloblastoma (MB) is the most common malignant pediatric brain tumor and group 3 subtype (G3-MB) exhibits the worst prognosis. Dissecting super-enhancer (SE) driven transcriptional dependencies of cancer has been shown to facilitate identifying novel oncogenic mechanisms and therapeutic targets or strategies. In this study, our integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB revealed their partially conserved SE-associated transcripts were enriched of subtype-specific tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized master TFs and eleven newly identified effector oncogenes. ARL4D, one of the effector oncogenes, was further demonstrated to exert its oncogenic role via maintaining cell-cycle progression and stemness of G3-MB cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector oncogene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB. Taken together, our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic targets or strategies.
2021-10-04 | GSE185024 | GEO
Project description:Medulloblastoma (MB) is the most common malignant pediatric brain tumor and group 3 subtype (G3-MB) exhibits the worst prognosis. Dissecting super-enhancer (SE) driven transcriptional dependencies of cancer has been shown to facilitate identifying novel oncogenic mechanisms and therapeutic targets or strategies. In this study, our integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB revealed their partially conserved SE-associated transcripts were enriched of subtype-specific tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized master TFs and eleven newly identified effector oncogenes. ARL4D, one of the effector oncogenes, was further demonstrated to exert its oncogenic role via maintaining cell-cycle progression and stemness of G3-MB cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector oncogene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB. Taken together, our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic targets or strategies.
2021-10-04 | GSE185003 | GEO
Project description:Dissecting Super-enhancer driven Transcriptional Dependencies Reveals Novel Oncogenes and Therapeutic Strategies of Group 3 Subtype Medulloblastoma
| PRJNA767390 | ENA
Project description:Dissecting Super-enhancer driven Transcriptional Dependencies Reveals Novel Oncogenes and Therapeutic Strategies of Group 3 Subtype Medulloblastoma [ChIP-seq]
| PRJNA767359 | ENA
Project description:Dissecting Super-enhancer driven Transcriptional Dependencies Reveals Novel Oncogenes and Therapeutic Strategies of Group 3 Subtype Medulloblastoma [RNA-seq]
| PRJNA767392 | ENA
Project description:Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
| S-EPMC4369477 | biostudies-literature
Project description:Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
| S-EPMC4201514 | biostudies-literature
Project description:Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
| S-EPMC3662966 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-12-27 | GSE134605 | GEO