Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti, Veronica; Giansanti, Manuela; Mitri, Francesca De; Gatto, Francesca; Mastronuzzi, Angela; Nazio, Francesca

doi:10.3389/fcell.2022.1007641

Cited by 6 publications

(8 citation statements)

References 167 publications

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“…Our findings demonstrate that MP1 not only inhibits MYC protein expression in MB, but also key pathways under its transcriptional control, such as cell cycle, protein synthesis/translation and metabolic pathways. Importantly, we and others have previously shown that mTOR/translation and metabolic pathways are highly activated in MYC-driven MB [ 23 , 37 ], which is consistent with MP1 having anticancer mechanism(s) that target these cellular pathways downstream of MYC. Together, these data suggest that MYC is the key target for MP1.…”

Section: Discussionsupporting

confidence: 82%

Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma

Coulter,

Chhonker,

Kumar

et al. 2024

J Exp Clin Cancer Res

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Background Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor prognoses and therapy resistance. However, MYC itself has been one of the most challenging targets for cancer treatment. Here, we identify a novel marinopyrrole natural derivative, MP1, that shows desirable anti-MYC and anti-cancer activities in MB. Methods In this study, using MYC-amplified (Group 3) and non-MYC amplified MB cell lines in vitro and in vivo, we evaluated anti-cancer efficacies and molecular mechanism(s) of MP1. Results MP1 significantly suppressed MB cell growth and sphere counts and induced G2 cell cycle arrest and apoptosis in a MYC-dependent manner. Mechanistically, MP1 strongly downregulated the expression of MYC protein. Our results with RNA-seq revealed that MP1 significantly modulated global gene expression and inhibited MYC-associated transcriptional targets including translation/mTOR targets. In addition, MP1 inhibited MYC-target metabolism, leading to declined energy levels. The combination of MP1 with an FDA-approved mTOR inhibitor temsirolimus synergistically inhibited MB cell growth/survival by downregulating the expression of MYC and mTOR signaling components. Our results further showed that as single agents, both MP1 and temsirolimus, were able to significantly inhibit tumor growth and MYC expression in subcutaneously or orthotopically MYC-amplified MB bearing mice. In combination, there were further anti-MB effects on the tumor growth and MYC expression in mice. Conclusion These preclinical findings highlight the promise of marinopyrrole MP1 as a novel MYC inhibition approach for MYC-amplified MB.

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Section: Discussionsupporting

confidence: 82%

Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma

Coulter,

Chhonker,

Kumar

et al. 2024

J Exp Clin Cancer Res

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“…Although MYC is associated with a glycolytic phenotype [ 10 , 43 – 45 ], stimulation of aerobic ATP production and anabolic pathways for biomass generation under normoxic conditions has been described [ 11 ]. In accordance, a recent review outlining metabolic characteristics of MB established thus far concluded that aerobic glycolysis and OXPHOS might be coexistent in MB [ 40 ]. Furthermore, the electron transport chain is closely linked to the metabolism of nucleotides [ 18 ].…”

Section: Discussionmentioning

confidence: 54%

“…Many factors influence cell metabolism, leading to diverse metabolic phenotypes even within one tumour entity [ 11 ]. While there have been other studies analysing metabolism in MB, we are only beginning to understand metabolic heterogeneity between MB groups [ 40 ]. Park et al, for example, established prognostically relevant metabolic pathways for SHH, G3 and G4 MB by exploring RNA expression data of the MAGIC cohort [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Group-specific cellular metabolism in Medulloblastoma

Funke,

Walter,

Melcher

et al. 2023

J Transl Med

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Background Cancer metabolism influences multiple aspects of tumorigenesis and causes diversity across malignancies. Although comprehensive research has extended our knowledge of molecular subgroups in medulloblastoma (MB), discrete analysis of metabolic heterogeneity is currently lacking. This study seeks to improve our understanding of metabolic phenotypes in MB and their impact on patients’ outcomes. Methods Data from four independent MB cohorts encompassing 1,288 patients were analysed. We explored metabolic characteristics of 902 patients (ICGC and MAGIC cohorts) on bulk RNA level. Moreover, data from 491 patients (ICGC cohort) were searched for DNA alterations in genes regulating cell metabolism. To determine the role of intratumoral metabolic differences, we examined single-cell RNA-sequencing (scRNA-seq) data from 34 additional patients. Findings on metabolic heterogeneity were correlated to clinical data. Results Established MB groups exhibit substantial differences in metabolic gene expression. By employing unsupervised analyses, we identified three clusters of group 3 and 4 samples with distinct metabolic features in ICGC and MAGIC cohorts. Analysis of scRNA-seq data confirmed our results of intertumoral heterogeneity underlying the according differences in metabolic gene expression. On DNA level, we discovered clear associations between altered regulatory genes involved in MB development and lipid metabolism. Additionally, we determined the prognostic value of metabolic gene expression in MB and showed that expression of genes involved in metabolism of inositol phosphates and nucleotides correlates with patient survival. Conclusion Our research underlines the biological and clinical relevance of metabolic alterations in MB. Thus, distinct metabolic signatures presented here might be the first step towards future metabolism-targeted therapeutic options. Graphical Abstract

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“…Tissue analysis of metabolites showed that MBs have higher lipid levels compared to other atypical teratoid/rhabdoid tumors [ 172 ]. It has been shown that MYCN could be a downstream target of the shh pathway in MB and its role in the regulation of glycolytic metabolism was studied in MB models [ 166 , 173 ]. However, the role of MYCN in the regulation of lipid metabolism still needs to be explored.…”

Section: Lipid Metabolism In Embryonal Tumorsmentioning

confidence: 99%

Lipid Metabolic Reprogramming in Embryonal Neoplasms with MYCN Amplification

Talapatra

Reddy

2023

Cancers

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Tumor cells reprogram their metabolism, including glucose, glutamine, nucleotide, lipid, and amino acids to meet their enhanced energy demands, redox balance, and requirement of biosynthetic substrates for uncontrolled cell proliferation. Altered lipid metabolism in cancer provides lipids for rapid membrane biogenesis, generates the energy required for unrestricted cell proliferation, and some of the lipids act as signaling pathway mediators. In this review, we focus on the role of lipid metabolism in embryonal neoplasms with MYCN dysregulation. We specifically review lipid metabolic reactions in neuroblastoma, retinoblastoma, medulloblastoma, Wilms tumor, and rhabdomyosarcoma and the possibility of targeting lipid metabolism. Additionally, the regulation of lipid metabolism by the MYCN oncogene is discussed.

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Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Cited by 6 publications

References 167 publications

Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma

Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma

Group-specific cellular metabolism in Medulloblastoma

Lipid Metabolic Reprogramming in Embryonal Neoplasms with MYCN Amplification

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