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TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216193 | GEO | 2026/02/01

REPOSITORIES: GEO

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TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

Project description:Current therapies for neuroblastoma, a pediatric tumor arising from immature sympathoblast progenitors of the peripheral sympathetic nervous system, are often ineffective and most survivors suffer from severe long-term therapy related side-effects, underscoring the need for identification of novel drugging strategies with limited toxicity. We performed for the first time an in-depth phenotypic and molecular evaluation of pharmacological eIF4A inhibition in neuroblastoma using the rocaglate CR31B, scrutinizing its mode-of-action through a comprehensive and integrated shotgun proteome profiling and combined ribosome/RNA-seq footprinting approach. Short-term treatment of neuroblastoma cells with CR31B significantly affected viability within the very low nanomolar concentration range. Notably, ribosome footprinting following short-term CR31B exposure (6 hours) revealed amongst others strong enrichment for transcripts encoding proteins involved in N-glycan biosynthesis amongst the downregulated hits, while upregulated targets are enriched for oxidative phosphorylation pathway components. Shotgun proteome profiles during long-term (24h-48h-72h) CR31B exposure revealed a strong enrichment of a FOXM1 driven signature amongst the downregulated hits, a key regulator implicated in cell cycle control and DNA damage response in neuroblastoma. Last, we could show that CR31B significantly reduces tumor growth in vivo without apparent toxicity in a neuroblastoma PDX model. In conclusion, we present CR31B as a potent novel potent therapeutic agent in neuroblastoma.

2026-02-01 | GSE216191 | GEO

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

2026-02-01 | GSE216192 | GEO

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma [MYCN_CutAndRun]

Project description:Current therapies for neuroblastoma are often ineffective and survivors suffer from severe long-term therapy related side-effects, underscoring the need for identification of novel drugging strategies. We performed an in-depth evaluation of phenotypic and molecular responses following exposure of neuroblastoma cells to the rocaglate CR-1-31-B, scrutinizing its mode-of-action through integrative ribosome footprinting and shotgun proteome profiling. We could show that CR-1-31-B significantly reduces tumor growth in vivo without apparent toxicity. By means of combined ribosome footprint and transcriptome analysis we could show that CR-1-31-B treatment induces downregulates factors involved in the G2/M checkpoint, while upregulated targets are enriched for oxidative phosphorylation pathway components and DNA repair. At the proteome level, CR-1-31-B revealed downregulation of a FOXM1 driven gene signature, with TPX2 as prominent marker. Knockdown of TPX2 leads to reduced neuroblastoma cell confluence and elevated levels of DNA damage. In conclusion, our data support CR-1-31-B as a potent novel therapeutic agent in neuroblastoma.

2026-02-01 | GSE246722 | GEO

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma[RNA-Seq]

2026-02-01 | GSE246725 | GEO

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

Project description:TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

| PRJNA892531 | ENA

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

Project description:TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

| PRJNA892548 | ENA

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

Project description:TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma

| PRJNA892545 | ENA

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma [MYCN_CutAndRun]

Project description:TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma [MYCN_CutAndRun]

| PRJNA1034494 | ENA

TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma[RNA-Seq]

Project description:TPX2 as key downstream target of the eIF4A controlled translational program in MYCN driven neuroblastoma[RNA-Seq]

| PRJNA1034495 | ENA

MYCN-targeting miRNAs are predominantly downregulated during MYCN‑driven neuroblastoma tumor formation.

Project description:MYCN is a transcription factor that plays key roles in both normal development and cancer. In neuroblastoma, MYCN acts as a major oncogenic driver through pleiotropic effects regulated by multiple protein encoding genes as well as microRNAs (miRNAs). MYCN activity is tightly controlled at the level of transcription and protein stability through various mechanisms. Like most genes, MYCN is further controlled by miRNAs, but the full complement of all miRNAs implicated in this process has not been determined through an unbiased approach. To elucidate the role of miRNAs in regulation of MYCN, we thus explored the MYCN-miRNA interactome to establish miRNAs controlling MYCN expression levels. We combined results from an unbiased and genome-wide high-throughput miRNA target reporter screen with miRNA and mRNA expression data from patients and a murine neuroblastoma progression model. We identified 29 miRNAs targeting MYCN, of which 12 miRNAs are inversely correlated with MYCN expression or activity in neuroblastoma tumor tissue. The majority of MYCN-targeting miRNAs in neuroblastoma showed a decrease in expression during murine MYCN-driven neuroblastoma tumor development. Therefore, we provide evidence that MYCN-targeting miRNAs are preferentially downregulated in MYCN-driven neuroblastoma, suggesting that MYCN negatively controls the expression of these miRNAs, to safeguard its expression.

| S-EPMC4467143 | biostudies-literature

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