Tumor suppressor miRNA inhibits medulloblastoma growth and sensitizes vincristine and radiation response by inducing spindle defects and DNA damage
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ABSTRACT:
PROVIDER: PRJNA414531 | ENA |
REPOSITORIES: ENA
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Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite recent improvements in overall survival, only a modest percentage of patients survive high-risk MB. The devastating side effects of radiation and chemotherapy substantially reduce qualify of life for surviving patients. We identified a novel tumor suppressor miRNA that sensitizes both ionizing radiation and vincristine responses in medulloblastoma. To understand the mechanism by which the tumor suppressor miR-584-5p may act as a tumor suppressor and therapy sensitizer, we performed microarray analysis in D425Med and D458Med medulloblastoma cells transfected with scrambled (miR-NC) or miR-584-5p mimic (miR-584-5p).
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Project description:Despite improvements in overall survival, only a modest percentage of patients survives high-risk medulloblastoma. The devastating side effects of radiation and chemotherapy substantially reduce quality of life for surviving patients. Here, using genomic screens, we identified miR-584-5p as a potent therapeutic adjuvant that potentiates medulloblastoma to radiation and vincristine. MiR-584-5p inhibited medulloblastoma growth and prolonged survival of mice in pre-clinical tumor models. MiR-584-5p overexpression caused cell cycle arrest, DNA damage, and spindle defects in medulloblastoma cells. MiR-584-5p mediated its tumor suppressor and therapy-sensitizing effects by targeting HDAC1 and eIF4E3. MiR-584-5p overexpression or HDAC1/eIF4E3 silencing inhibited medulloblastoma stem cell self-renewal without affecting neural stem cell growth. In medulloblastoma patients, reduced expression of miR-584-5p correlated with increased levels of HDAC1/eIF4E3. These findings identify a previously undefined role for miR-584-5p/HDAC1/eIF4E3 in regulating DNA repair, microtubule dynamics, and stemness in medulloblastoma and set the stage for a new way to treat medulloblastoma using miR-584-5p.
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Project description:Stable cisplatin- and vincristine-tolerant Group 3 and SHH cell lines were generated by continuous drug exposure with dose escalation to identify mechanisms driving resistance to standard-of-care medulloblastoma therapy. Next-generation sequencing revealed a vastly different transcriptomic landscape following chronic drug exposure, including a drug-tolerant gene expression signature, common to all sequenced drug-tolerant cell lines.
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Project description:Neuroblastoma and medulloblastoma are the most common solid tumors in children, with MYC(N) proto-oncogene amplification serving as a key marker of aggressive disease and poor treatment outcomes. However, the complex nature of the challenging MYC(N) protein underscores the urgent need for additional targets and therapies to tackle neuroblastoma and medulloblastoma. In this study, we identified FLIX5, a small compound that exhibits broad toxicity against both neuroblastoma and medulloblastoma cells by inducing apoptosis and ferroptosis. Furthermore, FLIX5 enhances the cholesterol dependency of neuroblastoma cells under conditions where mitochondrial function is impaired. FLIX5 as well synergistically enhances the effectiveness of conventional drugs vincristine and vinorelbine against neuroblastoma cells and patient-derived xenograft organoids. Through proteome integral solubility alteration, computational molecular docking predictions, and cellular thermal shift assays for target identification and validation, FLIX5 revealed EPLIN (Epithelial Protein Lost In Neoplasm) as a previously unexplored drug target. EPLIN functions as a tumor suppressor and plays roles in various cellular processes, including cholesterol uptake and mitochondrial activity. The discovery of FLIX5 targeting EPLIN opens new avenues for addressing the significant challenges posed by neuroblastoma and medulloblastoma, and potentially offering broader applications in other types of cancer.
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Project description:Gene expression profiles were assessed for vincristine-sensitive parental ovarian tumor cell line (SKOV3) and its highly vincristine-resistant derivative (SKVCR 2.0) Experiment Overall Design: Duplicate gene expression microarray experiments were undertaken for each of SKOV3 and SKVCR 2.0. Comparative analysis between these two groups defined genes activated in vincristine resistance
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Project description:Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of several cancer types. However, a main side-effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to decreased quality of life, changes in chemotherapeutic treatment or even treatment cessation. Although painful symptoms associated with CIPN are faithfully recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in peripheral sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia isolated from mice treated with vincristine, oxaliplatin, and cisplatin with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq using 75-nucleotide single end runs revealed 368, 295 and 256 differential expressed genes (DEGs) induced by treatment with vincristine, oxaliplatin and cisplatin, respectively. Although there were many similarities in DEGs between chemotherapeutic agents, only 5 genes were dysregulated in all groups. Cell type enrichment analysis (CTEA) and gene set enrichment analysis (GSEA) showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed inflammatory and neuropathic gene expression signature. Only ‘regulation of transport’ and ‘response to external stimuli’ were gene ontology terms shared between all treatments. These results provide insight into the recruitment of innate and adaptive immune responses to DRG tissue and indicate enhanced neuro-inflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.
2019-06-01 | GSE125001 | GEO
Project description:While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of STAT3. Furthermore, these senescent cells expand the repertoire of resistant cells by secreting an array of factors, including TGFb, which induce proliferating cells to exit mitosis and become quiescent—a state that is also insensitive to spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. We have incorporated our results into a model that explains how STAT3 and therapy induced senescence combine to drive resistance, which can provide insight into how to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma.
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Project description:The identity of the cell of origin is a key determinant of cancer subtype, progression and prognosis. Group 3 medulloblastoma (MB) is a malignant childhood brain cancer with poor prognosis and few candidates as putative cell of origin. We overexpressed the Group 3 MB genetic drivers MYC and Gfi1 in different candidate cells of origin in the postnatal mouse cerebellum. We found that S100b+ cells are competent to initiate Group 3 MB and we observed that S100b+ cells have higher levels of Notch1 pathway activity compared to Math1+ cells. Interestingly, we found that additional activation of Notch1 in Math1+ and Sox2+ cells was sufficient to induce Group 3 MB upon MYC/Gfi1 expression. Taken together, our data suggest that the Notch1 pathway plays a critical role in Group 3 MB initiation.
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