scholarly journals Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6100
Author(s):  
Tiziana Servidei ◽  
Donatella Lucchetti ◽  
Pierluigi Navarra ◽  
Alessandro Sgambato ◽  
Riccardo Riccardi ◽  
...  
Keyword(s):  
Adverse Outcome ◽  
Biological Processes ◽  
Developmental Origins ◽  
Cell Of Origin ◽  
Pediatric Malignancy ◽  
Patient Heterogeneity ◽  
Microenvironmental Factors ◽  
Potential Impact ◽  
Cellular Phenotypes ◽  
Embryonic Brain Development

Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.

scholarly journals ETMR-06. DISSECTING THE MOLECULAR AND DEVELOPMENTAL BASIS OF PINEOBLASTOMA THROUGH GENOMICS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii323-iii324
Author(s):  
Brian Gudenas ◽  
Bernhard Englinger ◽  
Anthony P Y Liu ◽  
Yiai Tong ◽  
David Meredith ◽  
...  
Keyword(s):  
Pineal Gland ◽  
Single Cell ◽  
Outcome Data ◽  
Genetically Engineered ◽  
Developmental Trajectory ◽  
Transcriptional Analysis ◽  
Molecular Heterogeneity ◽  
Developmental Origins ◽  
Cell Of Origin ◽  
Molecular Features

Abstract Pineoblastoma (PB) is an aggressive embryonal brain tumor comprising 1% of pediatric CNS tumors. The clinico-molecular heterogeneity and developmental origins underlying PB are poorly understood; therefore, we have assembled a molecular cohort of histologically defined PBs (n=43) with corresponding outcome data. Methylation profiling revealed four molecularly and clinically distinct PB subgroups, including two novel entities. Mutational and transcriptional analysis identified characteristic molecular features of each subgroup, such as mutations in the miRNA processing pathway or FOXR2 proto-oncogene overexpression. Furthermore, subgroups exhibited differences in propensity for metastasis, cytogenetics, and clinical outcomes. To dissect PB developmental origins and resolve PB subgroup biology, we have employed a combination of single-cell genomics and genetically engineered mouse modeling. We created a single-cell transcriptional atlas of the developing murine pineal gland across 11 timepoints and are currently integrating these data with single nuclei RNA-seq data of human PB (n=25). Single-cell analysis of the developing pineal gland revealed three distinct populations of pinealocytes, referred to as early, mid and late pinealocytes, which segregate by developmental stage yet lie along a single developmental trajectory. Preliminary results implicate significant associations between PBs and the early pinealocyte population as well as subgroup-specific differences in intratumoral heterogeneity. Furthermore, this knowledge has informed the downstream generation of biologically faithful disease models, including a transgenic mouse model of the PB-RB subgroup. Remarkably, this model shows up-regulation of key markers of PB such as Crx, Asmt and Otx2 and substantiates early pinealocytes as the probable cell-of-origin for this PB subgroup.

scholarly journals Analyzing Policies Through a DOHaD Lens: What Can We Learn?

2018 ◽  
Vol 15 (12) ◽  
pp. 2906 ◽  
Author(s):  
Julia Goodman ◽  
Janne Boone-Heinonen ◽  
Dawn Richardson ◽  
Sarah Andrea ◽  
Lynne Messer
Keyword(s):  
Life Course ◽  
Life Experiences ◽  
Evidence Base ◽  
Policy Impact ◽  
Full Potential ◽  
Developmental Origins ◽  
Health Trajectories ◽  
Health And Disease ◽  
Potential Impact ◽  
The Life Course

Social, health, and environmental policies are critical tools for providing the conditions needed for healthy populations. However, current policy analyses fall short of capturing their full potential impacts across the life course and from generation to generation. We argue that the field of Developmental Origins of Health and Disease (DOHaD), a conceptual and research framework positing that early life experiences significantly affect health trajectories across the lifespan and into future generations, provides an important lens through which to analyze social policies. To illustrate this point, we synthesized evidence related to policies from three domains—family leave, nutrition, and housing—to examine the health implications for multiple generations. We selected these policy domains because they represent increasing distance from a reproductive health focus, each with a growing evidence base to support a potential impact on pregnant women and their offspring. Each of these examples represents an opportunity to extend our understanding of policy impact using a DOHaD lens, taking into account the potential life course and intergenerational effects that have previously been overlooked.

scholarly journals Transcription factor binding dynamics shape noise across biological processes

2020 ◽  
Author(s):  
Lavisha Parab ◽  
Sampriti Pal ◽  
Riddhiman Dhar
Keyword(s):  
Transcription Factor ◽  
Large Fraction ◽  
Promoter Sequence ◽  
Quantitative Model ◽  
Cancer Drug ◽  
Biological Processes ◽  
Cellular Processes ◽  
Competition And Cooperation ◽  
Cancer Drug Resistance ◽  
Cellular Phenotypes

SummaryCellular processes driven by coordinated actions of individual genes generate cellular phenotypes. Stochastic variations in these processes lead to phenotypic heterogeneity that often has important implications for antibiotic persistence, mutation penetrance, cancer growth and anti-cancer drug resistance. However, the architecture of noise in cellular processes has remained largely unexplored even though expression noise in individual genes have been widely studied. Here we quantify noise in biological processes in yeast and through an integrated quantitative model show that the number of regulating transcription factors and their binding dynamics are the primary drivers of noise. Specifically, binding dynamics arising from competition and cooperation among TFs for promoter binding can predict a large fraction of noise variation. Our work reveals a novel mechanism of noise regulation that arises out of the dynamic nature of gene regulation and is not dependent on specific transcription factor or specific promoter sequence.

scholarly journals The Complexity of TET2 Functions in Pluripotency and Development

2021 ◽  
Vol 8 ◽  
Author(s):  
Vera Garcia-Outeiral ◽  
Cristina de la Parte ◽  
Miguel Fidalgo ◽  
Diana Guallar
Keyword(s):  
Transcriptional Regulation ◽  
Cell Fate ◽  
Normal Development ◽  
Tissue Homeostasis ◽  
Biological Processes ◽  
Chemical Modifications ◽  
Dna And Rna ◽  
Genome Regulation ◽  
Cellular Phenotypes ◽  
Post Transcriptional Regulation

Ten-eleven translocation-2 (TET2) is a crucial driver of cell fate outcomes in a myriad of biological processes, including embryonic development and tissue homeostasis. TET2 catalyzes the demethylation of 5-methylcytosine on DNA, affecting transcriptional regulation. New exciting research has provided evidence for TET2 catalytic activity in post-transcriptional regulation through RNA hydroxymethylation. Here we review the current understanding of TET2 functions on both DNA and RNA, and the influence of these chemical modifications in normal development and pluripotency contexts, highlighting TET2 versatility in influencing genome regulation and cellular phenotypes.

scholarly journals Enzyme Cytochemical Techniques for Metabolic Mapping in Living Cells, with Special Reference to Proteolysis

2001 ◽  
Vol 49 (12) ◽  
pp. 1473-1486 ◽  
Author(s):  
Emil Boonacker ◽  
Cornelis J.F. Van Noorden
Keyword(s):  
Living Cells ◽  
Biological Processes ◽  
Fluorogenic Substrates ◽  
Metabolic Mapping ◽  
Life And Death ◽  
Advantages And Disadvantages ◽  
Quantitative Manner ◽  
Activity Of Enzymes ◽  
Potential Impact ◽  
Endogenous Metabolites

Specific enzymes play key roles in many pathophysiological processes and therefore are targets for therapeutic strategies. The activity of most enzymes is largely determined by many factors at the post-translational level. Therefore, it is essential to study the activity of target enzymes in living cells and tissues in a quantitative manner in relation to pathophysiological processes to understand its relevance and the potential impact of its targeting by drugs. Proteases, in particular, are crucial in every aspect of life and death of an organism and are therefore important targets. Enzyme activity in living cells can be studied with various tools. These can be endogenous fluorescent metabolites or synthetic chromogenic or fluorogenic substrates. The use of endogenous metabolites is rather limited and nonspecific because they are involved in many biological processes, but novel chromogenic and fluorogenic substrates have been developed to monitor activity of enzymes, and particularly proteases, in living cells and tissues. This review discusses these substrates and the methods in which they are applied, as well as their advantages and disadvantages for metabolic mapping in living cells.

scholarly journals TMOD-28. NEW APPROACHES FOR ELUCIDATING MEDULLOBLASTOMA DEVELOPMENT VIA HINDBRAIN BLASTOCYST COMPLEMENTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii233-ii234
Author(s):  
Christin Schmidt ◽  
Annika Carlson ◽  
William Weiss ◽  
Bjoern Schwer
Keyword(s):  
Transgenic Mice ◽  
Time Window ◽  
Embryonic Stem ◽  
Genetically Engineered ◽  
Developmental Origins ◽  
Cell Of Origin ◽  
In Vivo Models ◽  
Immunodeficient Mice ◽  
Blastocyst Complementation

Abstract Understanding the etiology of brain cancers requires elucidation of developmental origins, genetic drivers, and the tumor microenvironment. This requires reliable in vivo approaches, which are currently lacking. Current in vivo models for pediatric brain tumors rely on generation of xenografts or allografts in immunodeficient mice or generation of transgenic mice. These approaches have severe limitations, including lack of a functional immune system, a restricted developmental time window defined by the cell of origin, or time-consuming workflows for the generation of transgenic mice. We recently developed neural blastocyst complementation (NBC), an organogenesis approach for the forebrain. NBC involves injection of donor mouse embryonic stem cells (ESC) into genetically-engineered blastocysts that are programmed to ablate dorsal telencephalic progenitors. This results in the formation of a donor-cell derived, intact forebrain. Based on this general approach, we are developing an in vivo platform for studies of brain cancer. We will report on our efforts and progress toward the generation of an organogenesis approach for the hindbrain and related studies that aim to define developmental origins and drivers of medulloblastoma.

Oxygen as a regulator of cellular phenotypes in pregnancy and cancer

2002 ◽  
Vol 80 (2) ◽  
pp. 103-109 ◽  
Author(s):  
Gendie E Lash ◽  
Lynne-Marie Postovit ◽  
Nicola E Matthews ◽  
Eugene Y Chung ◽  
Matthew T Canning ◽  
...  
Keyword(s):  
Tumour Progression ◽  
Antitumour Activity ◽  
Trophoblast Invasion ◽  
Cellular Phenotype ◽  
Low Oxygen ◽  
Microenvironmental Factors ◽  
Blastocyst Implantation ◽  
Cellular Behaviour ◽  
Cellular Phenotypes ◽  
Oxygenation Status

Cellular phenotype is determined by genetic and microenvironmental factors. There is evidence that tissue oxygenation status is one of the microenvironmental factors regulating cellular behaviour. Both normal and pathological processes such as blastocyst implantation in the uterus, placentation, and rapidly growing tumours occur under conditions characterized by relatively low oxygen levels. In this review, we address the effects of low oxygen concentrations on the phenotype of trophoblast and cancer cells. We provide evidence that oxygenation levels play an important role in the regulation of normal and pathological cellular invasiveness as it occurs during trophoblast invasion of the uterus and in tumour progression and metastasis, drug resistance in cancer, and antitumour activity of natural killer cells of the immune system.Key words: hypoxia, pregnancy, cancer.

scholarly journals COVID-19 engages clinical markers for the management of cancer and cancer-relevant regulators of cell proliferation, death, migration, and immune response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Serhiy Souchelnytskyi ◽  
Andriy Nera ◽  
Nazariy Souchelnytskyi
Keyword(s):  
Cell Proliferation ◽  
Immune System ◽  
Cancer Patients ◽  
Tumor Suppressors ◽  
Evidence Based ◽  
Biological Processes ◽  
Clinical Markers ◽  
Clinical Observations ◽  
Potential Impact ◽  
Selection Of

AbstractClinical reports show that the management of cancer patients infected with SARS-CoV-2 requires modifications. Understanding of cancer-relevant mechanisms engaged by the virus is essential for the evidence-based management of cancer. The network of SARS-CoV-2 regulatory mechanisms was used to study potential engagement of oncogenes, tumor suppressors, other regulators of tumorigenesis and clinical markers used in the management of cancer patients. Our network analysis confirms links between COVID-19 and tumorigenesis that were predicted in epidemiological reports. The COVID-19 network shows the involvement of tumorigenesis regulators and clinical markers. Regulators of cell proliferation, death, migration, and the immune system were retrieved. Examples are pathways initiated by EGF, VEGF, TGFβ and FGF. The SARS-CoV-2 network engages markers for diagnosis, prognosis and selection of treatment. Intersection with cancer diagnostic signatures supports a potential impact of the virus on tumorigenesis. Clinical observations show the diversity of symptoms correlating with biological processes and types of cells engaged by the virus, e.g. epithelial, endothelial, smooth muscle, glial and immune system cells. Our results describe an extensive engagement of cancer-relevant mechanisms and clinical markers by COVID-19. Engagement by the virus of clinical markers provides a rationale for clinical decisions based on these markers.

Fluorescent potentiometric dyes for membrane-potential imaging

1994 ◽  
Vol 52 ◽  
pp. 166-167
Author(s):  
Leslie M. Loew
Keyword(s):  
Membrane Potential ◽  
Single Cells ◽  
Quantitative Imaging ◽  
Optical Recording ◽  
Biological Processes ◽  
Major Focus ◽  
The Past ◽  
Excitable Systems ◽  
Major Application ◽  
The Impact

A major application of potentiometric dyes has been the multisite optical recording of electrical activity in excitable systems. After being championed by L.B. Cohen and his colleagues for the past 20 years, the impact of this technology is rapidly being felt and is spreading to an increasing number of neuroscience laboratories. A second class of experiments involves using dyes to image membrane potential distributions in single cells by digital imaging microscopy - a major focus of this lab. These studies usually do not require the temporal resolution of multisite optical recording, being primarily focussed on slow cell biological processes, and therefore can achieve much higher spatial resolution. We have developed 2 methods for quantitative imaging of membrane potential. One method uses dual wavelength imaging of membrane-staining dyes and the other uses quantitative 3D imaging of a fluorescent lipophilic cation; the dyes used in each case were synthesized for this purpose in this laboratory.

Apoptosis and development

2003 ◽  
Vol 39 ◽  
pp. 11-24 ◽  
Author(s):  
Justin V McCarthy
Keyword(s):  
Drosophila Melanogaster ◽  
Mammalian Cells ◽  
Cell Number ◽  
Model Organisms ◽  
Biological Processes ◽  
Nematode Caenorhabditis Elegans ◽  
Apoptotic Pathway ◽  
Genetic Pathways ◽  
Evolutionarily Conserved ◽  
Multicellular Organisms

Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The large diversity of regulators of apoptosis in mammalian cells and their numerous interactions complicate the analysis of their individual functions, particularly in development. The remarkable conservation of apoptotic mechanisms across species has allowed the genetic pathways of apoptosis determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, to act as models for understanding the biology of apoptosis in mammalian cells. Though many components of the apoptotic pathway are conserved between species, the use of additional model organisms has revealed several important differences and supports the use of model organisms in deciphering complex biological processes such as apoptosis.

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