Epigenetics in Clinical Management of Children and Adolescents with Brain Tumors

2017 ◽  
Vol 18 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Andres Morales La Madrid ◽  
Mark W. Kieran
Keyword(s):  
Nervous System ◽  
Brain Tumors ◽  
Children And Adolescents ◽  
Tumor Biology ◽  
Tumor Development ◽  
Integrated Approach ◽  
Cell Types ◽  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Molecular Profile

Central nervous system (CNS) tumors represent the second most prevalent group of cancers in children and adolescents, yet account for the majority of childhood cancer-related deaths and considerable morbidity among survivors, due to high-intensity non-selective standard therapies delivered to immature nervous system structures undergoing development. These tumors arise at different ages –not infrequently very early in life-, in different locations and cellular contexts, have varied cell types of origin, and have heterogeneous responses to the “classic” current therapeutic approaches. Demographic, radiologic and morphological characterization have several limitations, putting into the “classic boxes” heterogeneous tumors that are diverse in their genetic and epigenetic background and that will likely behave biologically different. Given that, epigenetic disruption (i.e. DNA methylation, histone modification and chromatin remodeling) is a common feature identified more and more frequently in pediatric cancer, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore tumor biology, evolution and treatment of these tumors. An integrated approach that incorporates traditional features complemented with genetic and epigenenetic specific markers offers tremendous promise to “risk-group” stratification and better prognostication. Also, it will help unveil the key driver pathways for tumor formation and for the discovery of targeted therapy for neoplasms that appear in the developing brain, facilitating early identification of therapy responders and track accurately disease progression. In this paper, we reviewed the most representative pediatric brain tumors where epigenetic alterations have been identified as initiating or driving events in tumor development, maintenance or progression.

scholarly journals Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yehuda Schlesinger ◽  
Oshri Yosefov-Levi ◽  
Dror Kolodkin-Gal ◽  
Roy Zvi Granit ◽  
Luriano Peters ◽  
...  
Keyword(s):  
Single Cell ◽  
Malignant Lesion ◽  
Tumor Development ◽  
Initial Step ◽  
Cell Types ◽  
Tumor Formation ◽  
Specific Cell ◽  
Preinvasive Lesions ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Abstract Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

Targeting BRAF in Pediatric Brain Tumors

2014 ◽  
pp. e436-e440 ◽  
Author(s):  
Mark W. Kieran
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tumors ◽  
Molecular Classification ◽  
Pediatric Brain Tumors ◽  
Feedback Loops ◽  
Braf V600e ◽  
Mutant Proteins ◽  
Pediatric Cancers ◽  
Pediatric Diseases

The role of BRAF in adult malignancy has been well documented over the last decade and recent data have extended these findings to a number of pediatric cancers. In this and the accompanying articles, we will review the importance of the BRAF pathway in signal transduction resulting in cell proliferation, migration, differentiation, and angiogenesis with a focus on three major pediatric diseases: brain tumors, Langerhans cell histiocytosis (LCH), and melanoma. Mutated BRAF proteins are being identified in an increasing number of pediatric cancers and the development of drugs that can target these mutant proteins offers enormous therapeutic opportunity for these diseases. Because of variations in the types of mutations of BRAF observed in different tumors, particularly those of the central nervous system, an understanding of the feedback loops that regulate monomeric and dimeric BRAF signaling will be critical in selecting the optimal targeted inhibitors. The two most commonly observed alterations in BRAF in patients with brain tumor are the BRAF V600E point mutation and the KIAA1549 truncated fusion and targeting of these will need to differ to account for these feedback loops. Many other factors will influence the activity of novel agents in BRAF activated tumors, including their ability to penetrate the blood-brain barrier (for brain tumors and some patients with LCH) as well as the development of drug resistance and toxicity profiles. Well-controlled trials that take these variables into consideration are already underway and highlight the need for molecular classification of pediatric central nervous system tumors.

scholarly journals SL1 GENETICS OF PEDIATRIC BRAIN TUMORS: RECENT ADVANCES AND FUTURE PERSPECTIVES

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
David T W Jones
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Somatic Hypermutation ◽  
Tumor Biology ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Enhancer Element ◽  
Frequent Mutations ◽  
Pediatric Brain

Abstract The last decade has seen a true revolution in our understanding of the oncogenic mechanisms underlying human tumors, brought about by transformative advances in the technologies available to interrogate the (epi)genetic composition of cancer cells. The dynamic pediatric neuro-oncology community has proven to be very agile in adapting to these changes, and has arguably been at the forefront of some of the most exciting new discoveries in tumor biology in recent years. For example, high-throughput genomic sequencing has revealed highly frequent mutations in histone genes in pediatric glioblastoma; highlighted an ever-expanding role for oncogenic gene fusions in multiple pediatric brain tumor types, and also shed light on novel phenotypic patterns such as chromothripsis (dramatic chromosomal shattering) and somatic hypermutation - the latter being a possible marker for response to novel immunotherapeutic approaches. Epigenetic profiling has also identified a role for ‘enhancer hijacking’ (whereby genomic rearrangement brings an active enhancer element in close proximity to a proto-oncogene) in multiple pediatric brain tumors, and is even pointing towards a fundamentally new way in which tumors may be molecularly classified. In coming years, the major challenge will be to harness the power of these discoveries to more accurately diagnose patients and to identify potential therapeutic targets in a more personalized way, so that these major biological advances can also be translated into substantial clinical benefit. Examples such as the dramatic responses observed in childhood brain tumor sufferers to BRAF V600E and NTRK inhibitors demonstrate the promise that such an approach can hold, but it will require a fundamental shift in the way that clinical trials are planned and conducted in order to optimize patient care. This talk will highlight some of the most striking developments in the field, and look at the challenges that remain before these can lead to improved patient outcomes.

scholarly journals Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Bruno Sainz ◽  
Emily Carron ◽  
Mireia Vallespinós ◽  
Heather L. Machado
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cross Talk ◽  
Tumor Biology ◽  
Cell Types ◽  
Tumor Formation ◽  
Self Renewal ◽  
Numerous Cell ◽  
Key Drivers

Cancer stem cells (CSCs) are a unique subset of cells within tumors with stemlike properties that have been proposed to be key drivers of tumor initiation and progression. CSCs are functionally defined by their unlimited self-renewal capacity and their ability to initiate tumor formationin vivo. Like normal stem cells, CSCs exist in a cellular niche comprised of numerous cell types including tumor-associated macrophages (TAMs) which provides a unique microenvironment to protect and promote CSC functions. TAMs provide pivotal signals to promote CSC survival, self-renewal, maintenance, and migratory ability, and in turn, CSCs deliver tumor-promoting cues to TAMs that further enhance tumorigenesis. Studies in the last decade have aimed to understand the molecular mediators of CSCs and TAMs, and recent advances have begun to elucidate the complex cross talk that occurs between these two cell types. In this review, we discuss the molecular interactions that define CSC-TAM cross talk at each stage of tumor progression and examine the clinical implications of targeting these interactions.

Epigenetic mechanisms regulating neural development and pediatric brain tumor formation

2011 ◽  
Vol 8 (2) ◽  
pp. 119-132 ◽  
Author(s):  
Claudia M. C. Faria ◽  
James T. Rutka ◽  
Christian Smith ◽  
Paul Kongkham
Keyword(s):  
Brain Tumors ◽  
Neural Development ◽  
Treatment Strategies ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Cancer Epigenetics ◽  
Development And Differentiation ◽  
Altered Gene ◽  
Pediatric Brain

Pediatric brain tumors are the leading cause of cancer-related death in children, and among them, embryonal tumors represent the largest group with an associated poor prognosis and long-term morbidity for survivors. The field of cancer epigenetics has emerged recently as an important area of investigation and causation of a variety of neoplasms, and is defined as alterations in gene expression without changes in DNA sequence. The best studied epigenetic modifications are DNA methylation, histone modifications, and RNA-based mechanisms. These modifications play an important role in normal development and differentiation but their dysregulation can lead to altered gene function and cancer. In this review the authors describe the mechanisms of normal epigenetic regulation, how they interplay in neuroembryogenesis, and how these can cause brain tumors in children when dysregulated. The potential use of epigenetic markers to design more effective treatment strategies for children with malignant brain tumors is also discussed.

scholarly journals Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives

2020 ◽  
Vol 10 (4) ◽  
pp. 254
Author(s):  
Sibylle Madlener ◽  
Johannes Gojo
Keyword(s):  
Brain Tumors ◽  
Liquid Biopsy ◽  
Current Knowledge ◽  
Clinical Care ◽  
Tumor Biology ◽  
Pediatric Brain Tumors ◽  
Genetic Alterations ◽  
Tumor Type ◽  
Molecular Alterations ◽  
Pediatric Brain

Tumors of the central nervous system are the most frequent solid tumor type and the major cause for cancer-related mortality in children and adolescents. These tumors are biologically highly heterogeneous and comprise various different entities. Molecular diagnostics are already well-established for pediatric brain tumors and have facilitated a more accurate patient stratification. The availability of targeted, biomarker-driven therapies has increased the necessity of longitudinal monitoring of molecular alterations within tumors for precision medicine-guided therapy. Nevertheless, diagnosis is still primarily based on analyses of the primary tumor and follow-up is usually performed by imaging techniques which lack important information on tumor biology possibly changing the course of the disease. To overcome this shortage of longitudinal information, liquid biopsy has emerged as a promising diagnostic tool representing a less-invasive source of biomarkers for tumor monitoring and therapeutic decision making. Novel ultrasensitive methods for detection of allele variants, genetic alterations with low abundance, have been developed and are promising tools for establishing and integrating liquid biopsy techniques into clinical routine. Pediatric brain tumors harbor multiple molecular alterations with the potential to be used as liquid biomarkers. Consequently, studies have already investigated different types of biomarker in diverse entities of pediatric brain tumors. However, there are still certain pitfalls until liquid biomarkers can be unleashed and implemented into routine clinical care. Within this review, we summarize current knowledge on liquid biopsy markers and technologies in pediatric brain tumors, their advantages and drawbacks, as well as future potential biomarkers and perspectives with respect to clinical implementation in patient care.

Thioredoxin, Glutathione and Related Molecules in Tumors of the Nervous System

2020 ◽  
Vol 27 (12) ◽  
pp. 1878-1900 ◽  
Author(s):  
Vasco Branco ◽  
José Pimentel ◽  
Maria Alexandra Brito ◽  
Cristina Carvalho
Keyword(s):  
Nervous System ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Malignant Tumors ◽  
Tumor Biology ◽  
Antioxidant Systems ◽  
Ros Scavenging ◽  
Survival Prognosis ◽  
Primary Tumors

Background: Central Nervous System (CNS) tumors have a poor survival prognosis due to their invasive and heterogeneous nature, in addition to the resistance to multiple treatments. Objective: In this paper, the main aspects of brain tumor biology and pathogenesis are reviewed both for primary tumors of the brain, (i.e., gliomas) and for metastasis from other malignant tumors, namely lung cancer, breast cancer and malignant melanoma which account for a high percentage of overall malignant brain tumors. We review the role of antioxidant systems, namely the thioredoxin and glutathione systems, in the genesis and/or progression of brain tumors. Methods: Although overexpression of Thioredoxin Reductase (TrxR) and Thioredoxin (Trx) is often linked to increased malignancy rate of brain tumors, and higher expression of Glutathione (GSH) and Glutathione S-Transferases (GST) are associated to resistance to therapy, several knowledge gaps still exist regarding for example, the role of Peroxiredoxins (Prx), and Glutaredoxins (Grx). Conclusion: Due to their central role in redox homeostasis and ROS scavenging, redox systems are potential targets for new antitumorals and examples of innovative therapeutics aiming at improving success rates in brain tumor treatment are discussed.

scholarly journals TMOD-02. GEBTO: GENETICALLY ENGINEERED BRAIN TUMOR ORGANOIDS AS A NOVEL PRECLINICAL MODEL

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i35-i36
Author(s):  
Jens Bunt ◽  
Mieke Roosen ◽  
Evie Egelmeers ◽  
Joris Maas ◽  
Zelda Ode ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Biology ◽  
Embryonic Stem ◽  
Pediatric Brain Tumors ◽  
Genetically Engineered ◽  
Preclinical Model ◽  
Cells Of Origin ◽  
Pediatric Brain ◽  
Tumor Organoids

Abstract Background One of the bottlenecks in basic and translational research on pediatric brain tumors, is the lack of suitable and representative preclinical models to study tumor biology and drug sensitivity. Over the last decades, extensive molecular characterization has uncovered many entities and subgroups with their unique oncodriving events. However, this heterogeneity is currently not reflected in the models available, especially not for in vitro models. Objectives We aim to generate genetically engineered brain tumor organoids (GEBTO) to represent the molecular variety of embryonal brain tumors and ependymomas. Method Human brain organoids derived from embryonic stem cells are generated to represent the region of tumor origin. To mimic oncodriving events, DNA plasmids are introduced via electroporation in the organoid cells to knockout tumor suppressor genes or overexpress oncogenes. Results Cerebellar and cerebral forebrain organoids were generated as the tissue of origin for medulloblastoma and supratentorial ependymoma (ST-EPN), respectively. Based on the detection of GFP protein encoded by DNA plasmids, the organoid cells can be manipulated within a wide developmental window, which corresponds with the presence of the proposed cells of origin. Different oncodrivers and combinations thereof are now being tested to see whether they result in ectopic growth in cerebral or cerebellar organoids. When successful, the GEBTOs are histologically and molecularly characterized using (single cell) transcriptomic and epigenomic analyses to see how well they resemble human tumors. Discussion Although further development is required, GEBTOs provide a novel avenue to model especially rare pediatric brain tumors, for which tissue and therefore patient-derived models are limited. It also allows for in-depth analyses of the potential cells of origin and the contribution of different mutations to tumor biology.

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