Cancer astrocytes have a more conserved molecular status in long recurrence free survival (RFS) IDH1 wild-type glioblastoma patients: new emerging cancer players

Franceschi, Sara; Lessi, Francesca; Aretini, Paolo; Ortenzi, Valerio; Scatena, Cristian; Menicagli, Michele; Ferla, Marco La; Civita, Prospero; Zavaglia, Katia; Scopelliti, Claudia; Apollo, Alessandro; Carbone, Francesco; Vannozzi, Riccardo; Bevilacqua, Generoso; Pasqualetti, Francesco; Naccarato, Antonio Giuseppe; Mazzanti, Chiara Maria

doi:10.18632/oncotarget.25265

Cited by 8 publications

(10 citation statements)

References 57 publications

(53 reference statements)

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“…We previously used whole-transcriptome RNA sequencing [ 17 ] to analyze 13 newly diagnosed cases of primary FFPE (formalin-fixed and paraffin-embedded) GBM, specifically selected for different length of recurrence-free survival time (RFS). We defined three groups: the short-term group (S) with RFS < 6 months ( n = 6), the medium term group (M) with 16 < RFS < 23 months ( n = 3) and the long-term group (L) with RFS > 25 months ( n = 4).…”

Section: Resultsmentioning

confidence: 99%

“…GLUD2 initially emerged from our previous NGS analysis [ 17 ] conducted on 13 GBM samples from patients with different recurrence time (RFS). GLUD2 was overexpressed in the tumors of patients with long RFS.…”

Section: Discussionmentioning

confidence: 99%

“…NGS and microarray analysis data were obtained from our previous paper [ 17 ] and the Gene Expression Omnibus (GEO) GSE4271 dataset [ 18 ] respectively, together with molecular and clinical information. In particular, NGS analysis was performed on FFPE tumor tissues from 13 primary human GBM subjects selected from the archives of the Anatomy Pathology Institute of the University of Pisa, Italy.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression

et al. 2018

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BackgroundGlioblastoma (GBM) is the most frequent and malignant primary brain tumor in adults and despite the progress in surgical procedures and therapy options, the overall survival remains very poor. Glutamate and α-KG are fundamental elements necessary to support the growth and proliferation of GBM cells. Glutamate oxidative deamination, catalyzed by GLUD2, is the predominant pathway for the production of α-KG.MethodsGLUD2 emerged from the RNA-seq analysis of 13 GBM patients, performed in our laboratory and a microarray analysis of 77 high-grade gliomas available on the Geo database. Thereafter, we investigated GLUD2 relevance in cancer cell behavior by GLUD2 overexpression and silencing in two different human GBM cell lines. Finally, we overexpressed GLUD2 in-vivo by using zebrafish embryos and monitored the developing central nervous system.FindingsGLUD2 expression was found associated to the histopathological classification, prognosis and survival of GBM patients. Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production. In support of these findings, we also demonstrated, with in-vivo studies, that GLUD2 overexpression affects glial cell proliferation without affecting neuronal development in zebrafish embryos.InterpretationWe concluded that GLUD2 overexpression inhibited GBM cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression

et al. 2018

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“…Similarly, metabolism affects heterogeneity in GBM; indeed, the hypoxic tumour microenvironment supports CSCs self-renewal, proliferation, and survival. IDH1 mutations represent an interesting link between genetics and metabolism in GBM, causing accumulation of 2-hydroxyglutarate, thus promoting aberrant hypermethylation of DNA and histones, and dedifferentiation [ 232 , 233 , 234 , 235 , 236 , 237 , 238 ].…”

Section: Cancer Stem Cells and Tumor Microenvironmentmentioning

confidence: 99%

Decipher the Glioblastoma Microenvironment: The First Milestone for New Groundbreaking Therapeutic Strategies

Fanelli

Grassini

Ortenzi³

et al. 2021

Genes

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Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite the combination of novel therapeutical approaches, it remains a deadly malignancy with an abysmal prognosis. GBM is a polymorphic tumour from both molecular and histological points of view. It consists of different malignant cells and various stromal cells, contributing to tumour initiation, progression, and treatment response. GBM’s microenvironment is multifaceted and is made up of soluble factors, extracellular matrix components, tissue-resident cell types (e.g., neurons, astrocytes, endothelial cells, pericytes, and fibroblasts) together with resident (e.g., microglia) or recruited (e.g., bone marrow-derived macrophages) immune cells. These latter constitute the so-called immune microenvironment, accounting for a substantial GBM’s tumour volume. Despite the abundance of immune cells, an intense state of tumour immunosuppression is promoted and developed; this represents the significant challenge for cancer cells’ immune-mediated destruction. Though literature data suggest that distinct GBM’s subtypes harbour differences in their microenvironment, its role in treatment response remains obscure. However, an in-depth investigation of GBM’s microenvironment may lead to novel therapeutic opportunities to improve patients’ outcomes. This review will elucidate the GBM’s microenvironment composition, highlighting the current state of the art in immunotherapy approaches. We will focus on novel strategies of active and passive immunotherapies, including vaccination, gene therapy, checkpoint blockade, and adoptive T-cell therapies.

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“…Tumor heterogeneity is one of the main reasons for the poor prognosis and overall survival due to therapeutic failure and drug-resistance [ 1 , 3 , 11 , 12 , 13 ]; therefore, it represents a challenge to achieve the goals of precision medicine. This raises the important question of whether the molecular characterization of a single portion of the tumor sufficiently represents the genomic landscape of GB in a biologically and clinically significant way for personalized-medicine approaches.…”

Section: Introductionmentioning

confidence: 99%

Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History

Franceschi

Civita

Pasqualetti

et al. 2021

Cancers

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Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option.

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Cancer astrocytes have a more conserved molecular status in long recurrence free survival (RFS) IDH1 wild-type glioblastoma patients: new emerging cancer players

Cited by 8 publications

References 57 publications

Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression

Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression

Decipher the Glioblastoma Microenvironment: The First Milestone for New Groundbreaking Therapeutic Strategies

Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History

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