MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Tao, Ling; Mohammad, Mahmoud A.; Milazzo, Giorgio; Moreno‐Smith, Myrthala; Patel, Tajhal; Zorman, Barry; Badachhape, Andrew; Hernandez, Blanca E; Wolf, Amber B; Zeng, Zihua; Foster, Jennifer; Aloisi, Sara; Sumazin, Pavel; Zu, Youli; Hicks, John; Ghaghada, Ketan B.; Putluri, Nagireddy; Perini, Giovanni; Coarfa, Cristian; Barbieri, Eveline

doi:10.1038/s41467-022-31331-2

Cited by 31 publications

(34 citation statements)

References 72 publications

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“…Neuroblastoma and, in particular, MYCN amplified tumors are heavily dependent in glutamine, and blocking MYCN leads to the arrest of glutamine transport [ 177 , 178 ]. In addition, MYCN promotes the glycolysis and fatty acid uptake and leads to mitochondria alteration [ 178 , 179 ]. MNA tumors also present different metabolic alterations, leading to an increase in iron uptake.…”

Section: Mycn Determines High-risk Neuroblastomamentioning

confidence: 99%

MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment

Bartolucci

Montemurro

Raieli³

et al. 2022

Cancers

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Among childhood cancers, neuroblastoma is the most diffuse solid tumor and the deadliest in children. While to date, the pathology has become progressively manageable with a significant increase in 5-year survival for its less aggressive form, high-risk neuroblastoma (HR-NB) remains a major issue with poor outcome and little survivability of patients. The staging system has also been improved to better fit patient needs and to administer therapies in a more focused manner in consideration of pathology features. New and improved therapies have been developed; nevertheless, low efficacy and high toxicity remain a staple feature of current high-risk neuroblastoma treatment. For this reason, more specific procedures are required, and new therapeutic targets are also needed for a precise medicine approach. In this scenario, MYCN is certainly one of the most interesting targets. Indeed, MYCN is one of the most relevant hallmarks of HR-NB, and many studies has been carried out in recent years to discover potent and specific inhibitors to block its activities and any related oncogenic function. N-Myc protein has been considered an undruggable target for a long time. Thus, many new indirect and direct approaches have been discovered and preclinically evaluated for the interaction with MYCN and its pathways; a few of the most promising approaches are nearing clinical application for the investigation in HR-NB.

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Section: Mycn Determines High-risk Neuroblastomamentioning

confidence: 99%

MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment

Bartolucci

Montemurro

Raieli³

et al. 2022

Cancers

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“…Fatty acid metabolism has been proven to contribute to multiple processes of cancer development, including tumor initiation, distant metastasis, recurrence and treatment failure (Cheng et al, 2022;Shueng et al, 2022;Tao et al, 2022;Wilcock et al, 2022). Dysregulated expression of FA-related genes were major contributors to the obstacle of fatty acid metabolism (Zhao et al, 2017;Liu et al, 2019;Park et al, 2019;Zhao F. et al, 2021;Zhou et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance and immune landscape of a fatty acid metabolism-related gene signature in colon adenocarcinoma

et al. 2022

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Background: Fatty acid metabolism (FAM), as a hallmark of caner, plays important roles in tumor initiation and carcinogenesis. However, the significance of fatty acid metabolism-related genes in colon adenocarcinoma (COAD) are largely unknown.Methods: RNA sequencing data and clinical information were downloaded from the Cancer Genome Atlas (TCGA) cohort. Univariate and multivariate Cox regression analyses were utilized to construct a fatty acid metabolism-related gene signature. Kaplan-Meier survival and receiver operating characteristic (ROC) analyses were used to verify the performance of this signature. GEO datasets were applied to validate the signature. Maftools package was utilized to analyze the mutation profiles of this signature. Correlation between the risk signature and stemness scores was compared by RNA stemness score (RNAss). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set variation analysis (GSVA) were performed to explore the potential functions and signaling pathways. Immune landscape of the signature was explored by analyzing different immune cells infiltration, immune functions and microsatellite instability. A nomogram was constructed by combining the risk signature and multiple clinical factors. Expression levels and prognostic values of the risk genes were revealed in the cancer genome atlas and GEO databases. Moreover, the expression the risk genes were measured in cell lines using real time quantitative PCR (qRT-PCR).Results: Eight fatty acid metabolism-related genes (CD36, ENO3, MORC2, PTGR1, SUCLG2, ELOVL3, ELOVL6 and CPT2) were used to construct a risk signature. This signature demonstrated better prognostic value than other clinicopathological parameters, with AUC value was 0.734 according to the cancer genome atlas database. There was negative correlation between the riskscore and RNA stemness score. The patients in the high-risk group demonstrated higher infiltration of M0 macrophages, and less infiltration of activated CD4 memory T cells and Eosinophils. There were more MSI patients in the high-risk group than those in the low-risk group (38% vs. 30%). The risk scores of patients in the MSI group were slightly higher than those in the microsatellite stability group. Gene ontology, kyoto encyclopedia of genes and genomes and gene set variation analysis enrichment analyses showed that several metabolism-related functions and signaling pathways were enriched. A nomogram showed good predictive capability of the signature. Moreover, qRT-PCR revealed upregulated expression of ENO3, MORC2, SUCLG2 and ELOVL6, and downregulated expression of CPT2 in all examined colon adenocarcinoma cell lines.Conclusion: This study provided novel insights into a fatty acid metabolism-related signature in the prognosis an immune landscape of colon adenocarcinoma patients.

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“…The MYCN oncogene, similar to its paralog c-MYC, regulates multiple metabolic pathways in RB, NB, and other tumors [ 40 , 44 , 45 ]. The role of metabolic reprogramming in NB is extensively studied compared to other tumors with MYCN amplification [ 46 ].…”

Section: Metabolic Reprogramming In Cancer and Mycnmentioning

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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MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Cited by 31 publications

References 72 publications

MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment

MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment

Prognostic significance and immune landscape of a fatty acid metabolism-related gene signature in colon adenocarcinoma

Lipid Metabolic Reprogramming in Embryonal Neoplasms with MYCN Amplification

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