Lipid saturation homeostasis presents a targetable vulnerability in MYC-amplified Group 3 medulloblastoma
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ABSTRACT:
PROVIDER: PRJNA1087610 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28341536_1.fastq.gz | Fastqsanger.gz | |||
| SRR28341536_2.fastq.gz | Fastqsanger.gz | |||
| SRR28341537_1.fastq.gz | Fastqsanger.gz | |||
| SRR28341537_2.fastq.gz | Fastqsanger.gz | |||
| SRR28341538_1.fastq.gz | Fastqsanger.gz |
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Project description:Medulloblastoma (MB) is the most common malignant pediatric brain cancer, originating from the cerebellum. Despite advancements in standard of care (SoC), MB remains fatal for 30% of patients. Tumor relapse, spinal metastasis and treatment resistance are the most prevalent in MYC-driven Group 3 MB (G3-MB). Patients surviving SoC are faced with life-long neurocognitive and neurodevelopmental deficits. These issues highlight the urgent need for improved treatment modalities. Reprogramming of cellular lipid metabolism is an emerging hallmark of cancer and may yield novel cancer-specific therapeutic options. Here we explore the lipidome of both G3-MB and its proposed cell of origin, human neural stem cells (hNSCs) by comparing untargeted lipidomics using Liquid-Chromatography-Mass Spectrometry (LC-MS). Comparative analyses revealed a differential abundance of distinct lipid species in G3-MB, with an overall reduced saturation level of fatty acids (FAs). These findings implicate the de novo lipid synthesis (DNL) pathway. We identified the enzymes involved in DNL to be essential for MB survival in our genome-wide CRISPR KO screen. Additionally, mRNA expression of the DNL enzymes increases at relapse in our SoC-adapted murine patient-derived xenograft (PDX) model. Pharmacological and genetic targeting of the DNL enzyme Stearoyl-CoA Desaturase 1 (SCD1) selectively targets G3-MB. Furthermore, small molecule treatment of SCD1 demonstrates efficacy against G3-MB PDX models in vivo. We identified SCD expression as a prognostic marker in Group 3 and 4 MB patients and identified possible pathways for MB treatment. Overall, these findings indicate that SCD1 is a potent target for the treatment of G3-MB.
2024-09-01 | GSE261568 | GEO
Project description:Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the anti-ferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc-. The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.
| S-SCDT-10_15252-EMMM_202318014 | biostudies-other
Project description:Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma
| PRJNA887081 | ENA
Project description:Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.
| S-EPMC10689432 | biostudies-literature
Project description:Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog-activated (SHH-activated) MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MB developing in p53-deficient Ptch+/- SHH mice that, unexpectedly, showed LC/A traits that correlated with mTORC1 hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/- SHH MB and CSC-derived MB resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patient samples, and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.
| S-EPMC8675203 | biostudies-literature
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 |
Project description:Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [EPIC]
| PRJNA887097 | ENA
Project description:Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma. [CRISPRseq]
| PRJNA887789 | ENA
Project description:MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC-driven MBs to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. We here characterize the transcriptional effects of class I HDAC inhibition in MYC-driven MB and explore beneficial drug combinations. MYC-amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile compared to untreated control were quantified on a microarray. Gene set enrichment analysis, cytoscape enrichment mapping and ingenuity pathway analysis led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested as single agents in metabolic activity assays in three MYC-amplified and two non-MYC-amplified MB cell lines. Synergy with entinostat was evaluated by dose response curve shift, combination index and zero interaction potency synergy model and validated in cell count and flow cytometry experiments in two MYC-amplified and one non-MYC-amplified MB cell line. The effect of the most promising drug combination (entinostat and olaparib) on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry. Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat. The combination of entinostat and olaparib led to increased cell death, decreased viability and increased formation of double strand breaks selectively in MYC-amplified MB cells. MYC-amplified MB cells treated with entinostat and olaparib were particularly vulnerable to additional induction of DNA damage by doxorubicin. Non-MYC-amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment. Our study identifies the combination of entinostat with olaparib and doxorubicin as a new potential therapeutic approach for MYC-driven Group 3 MB.
2023-10-04 | GSE232148 | GEO
Project description:Illumina HT-12 v4 microarrays were used to measure genome-wide gene expression in peripheral blood from occupational offshore divers, all male and fulfilling the criteria for diving personnel set in the NORSOK U-100 standard for manned underwater operations. Saturation dives lasted 13 - 20 days, with maximal diving depths 100 - 125 mws. Elevated oxygen during deep saturation dives triggers oxidative stress. To test the effects of oral antioxidants on post-dive gene expression, the divers were divided into two groups: one group (13 divers) received daily supplementation of antioxidant vitamins C (500mg/day) and E (200mg/day) during their dives, the other (7 divers) was not.
2017-09-30 | E-MTAB-4491 | biostudies-arrayexpress