Neurotrophin Signaling in Medulloblastoma

Thomaz, Amanda Cristina Godot; Jaeger, Mariane da Cunha; Brunetto, Algemir Lunardi; Brunetto, Andre Tessainer; Gregianin, Lauro José; Farias, Caroline Brunetto de; Ramaswamy, Vijay; Nör, Carolina; Taylor, Michael D.; Roesler, Rafaël

doi:10.3390/cancers12092542

Cited by 30 publications

(20 citation statements)

References 139 publications

(208 reference statements)

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“…Collectively, it can be deduced that NT5C2 plays a crucial role in the development and functional maintenance of neurosystem. Up to our knowledge, the NGF/TrkA signaling could participate in the process of cell survival, proliferation, and migration through at least three pathways, namely, RAS/RAF/MEK/ERK, PI3K/Akt, and PLC/PCK ( Thomaz et al, 2020 ; Esteban-Villarrubia et al, 2020 ). Through in silico analysis, we found that there were multiple binding sites of transcriptional factors such as STAT1β, ELK1, and NF-κB at the upstream promoter region of NT5C2 gene ( Supplementary Material 1 ), and all these factors are associated with at least one of the above pathways (27).…”

Section: Discussionmentioning

confidence: 99%

Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis

Yang

Hu³

et al. 2021

Front. Genet.

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Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused mainly by biallelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation.Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation. Subsequently, an in silico molecular dynamic (MD) analysis was performed to explore the intramolecular impact of the novel missense variant. Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid chromatography–mass spectrometry (LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR).Results: A novel compound heterozygous variation in NTRK1 gene was detected, consisting of the c.851–33T > A and c.2242C > T (p.Arg748Trp) variants. MD result suggested that p.Arg748Trp could affect the intramolecular structure stability. The results of the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA level.Conclusion: The findings in this study extended the variation spectrum of NTRK1, provided evidence for counseling to the affected family, and offered potential clues and biomarkers to the pathogenesis of CIPA.

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Section: Discussionmentioning

confidence: 99%

Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis

Yang

Hu³

et al. 2021

Front. Genet.

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“…The Notch, Wnt/β-catenin, and Hedgehog signaling pathways are additional conserved pathways that play important roles in NSC regulation throughout typical brain development and that also appear to have a role in medulloblastoma CSC maintenance and represent possible therapeutic targets (Figure 3). There are likely to be other pathways in normal neural development whose relationship with CSCs should be studied, such as neurotrophin signaling [52].…”

Section: Relationship Between Brain Tumor Cancer Stem Cells and Neural Stem Cellsmentioning

confidence: 99%

Overview and recent advances in the targeting of medulloblastoma cancer stem cells

Paul

Zage

2021

Expert Review of Anticancer Therapy

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Introduction: Medulloblastoma, an embryonal small round blue cell tumor primarily arising in the posterior fossa, is the most common malignancy of the central nervous system in children and requires intensive multi-modality therapy for cure. Overall 5-year survival is approximately 75% in children with primary disease, but outcomes for relapsed disease are very poor. Recent advances have identified molecular subgroups with excellent prognosis, with 5-year overall survival rates >90%, and subgroups with very poor prognosis with overall survival rates <50%. Molecular subtyping has allowed for more sophisticated risk stratification of patients, but new treatments for the highest risk patients have not yet improved outcomes. Targeting cancer stem cells may improve outcomes, and several candidate targets and novel drugs are under investigation. Areas covered: We discuss medulloblastoma epidemiology, biology, treatment modalities, risk stratification, and molecular subgroup analysis, links between subgroup and developmental biology, cancer stem cell biology in medulloblastoma including previously described cancer stem cell markers and proposed targeted treatments in the current literature. Expert opinion: The understanding of cancer stem cells in medulloblastoma will advance therapies targeting the most treatment-resistant cells within the tumor and therefore reduce the incidence of treatment refractory and relapsed disease.

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“…Although multimodal treatments with surgery radiotherapy and chemotherapy has improved cure rates, about one-third of patients relapse, and survivors experience long-lasting neurological, cognitive, and endocrinological sequelae. Thus, the development of molecularly targeted therapies is urgently needed [55][56][57][58].…”

Section: G9a and Medulloblastomamentioning

confidence: 99%

EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

Souza

Freire

Jaeger

et al. 2021

IJMS

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Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

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Neurotrophin Signaling in Medulloblastoma

Cited by 30 publications

References 139 publications

Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis

Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis

Overview and recent advances in the targeting of medulloblastoma cancer stem cells

EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

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