scholarly journals The evolution of the cancer stem cell state in glioblastoma: emerging insights into the next generation of functional interactions

2020 ◽  
Author(s):  
Kelly Mitchell ◽  
Katie Troike ◽  
Daniel J Silver ◽  
Justin D Lathia
Keyword(s):  
Cellular Heterogeneity ◽  
Next Generation ◽  
Cell State ◽  
Functional Interactions ◽  
Current State ◽  
Key Concepts ◽  
Discrete Population ◽  
A Cell ◽  
Stem Cell State ◽  
Primary Malignant Brain Tumor

Abstract Cellular heterogeneity is a hallmark of advanced cancers and has been ascribed in part to a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). Glioblastoma (GBM), the most common primary malignant brain tumor, has served as a platform for the study of CSCs. In addition to illustrating the complexities of CSC biology, these investigations have led to a deeper understanding of GBM pathogenesis, revealed novel therapeutic targets, and driven innovation towards the development of next-generation therapies. While there continues to be an expansion in our knowledge of how CSCs contribute to GBM progression, opportunities have emerged to revisit this conceptual framework. In this review, we will summarize the current state of CSCs in GBM using key concepts of evolution as a paradigm (variation, inheritance, selection, and time) to describe how the CSC state is subject to alterations of cell intrinsic and extrinsic interactions that shape their evolutionarily trajectory. We identify emerging areas for future consideration, including appreciating CSCs as a cell state that is subject to plasticity, as opposed to a discrete population. These future considerations will not only have an impact on our understanding of this ever-expanding field but will also provide an opportunity to inform future therapies to effectively treat this complex and devastating disease.

scholarly journals CellTrans: An R Package to Quantify Stochastic Cell State Transitions

2017 ◽  
Vol 11 ◽  
pp. 117793221771224 ◽  
Author(s):  
Thomas Buder ◽  
Andreas Deutsch ◽  
Michael Seifert ◽  
Anja Voss-Böhme
Keyword(s):  
Cell Lines ◽  
Transition Probabilities ◽  
Cell Lineage ◽  
R Package ◽  
State Transitions ◽  
Cell State ◽  
Current State ◽  
Cancerous Cell ◽  
Distinct Cell ◽  
A Cell

Many normal and cancerous cell lines exhibit a stable composition of cells in distinct states which can, e.g., be defined on the basis of cell surface markers. There is evidence that such an equilibrium is associated with stochastic transitions between distinct states. Quantifying these transitions has the potential to better understand cell lineage compositions. We introduce CellTrans, an R package to quantify stochastic cell state transitions from cell state proportion data from fluorescence-activated cell sorting and flow cytometry experiments. The R package is based on a mathematical model in which cell state alterations occur due to stochastic transitions between distinct cell states whose rates only depend on the current state of a cell. CellTrans is an automated tool for estimating the underlying transition probabilities from appropriately prepared data. We point out potential analytical challenges in the quantification of these cell transitions and explain how CellTrans handles them. The applicability of CellTrans is demonstrated on publicly available data on the evolution of cell state compositions in cancer cell lines. We show that CellTrans can be used to (1) infer the transition probabilities between different cell states, (2) predict cell line compositions at a certain time, (3) predict equilibrium cell state compositions, and (4) estimate the time needed to reach this equilibrium. We provide an implementation of CellTrans in R, freely available via GitHub ( https://github.com/tbuder/CellTrans ).

scholarly journals A lncRNA/Lin28/Mirlet7 axis coupled to DNA methylation fine tunes the dynamics of a cell state transition

2017 ◽  
Author(s):  
Meng Amy Li ◽  
Paulo P. Amaral ◽  
Priscilla Cheung ◽  
Jan H. Bergmann ◽  
Masaki Kinoshita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
State Transition ◽  
De Novo ◽  
Embryonic Stem ◽  
Lineage Specification ◽  
Cell State ◽  
Non Coding Rna ◽  
A Cell ◽  
Long Non Coding Rna ◽  
Stem Cell State

SummaryExecution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a condition poised for lineage specification. This process is controlled at transcriptional, post-transcriptional and epigenetic levels and non-coding RNAs are contributors to this regulation complexity. Here we identify a molecular cascade initiated by a long non-coding RNA (lncRNA), Ephemeron (Epn), that modulates the dynamics of exit from naïve pluripotency. Epn deletion delays the extinction of ESC identity, an effect mediated by perduring expression of the pivotal transcription factor Nanog. In the absence of Epn, Lin28a expression is reduced, resulting in an elevated level of Mirlet7g that suppresses de novo methyltransferases Dnmt3a/b. Dnmt3a/b deletion also retards exit from the ESC state, and is associated with delayed promoter methylation and slower down-regulation of Nanog. Altogether, our findings reveal a lncRNA/miRNA/DNA methylation axis that facilitates a timely stem cell state transition.

Minority Presidents in a Coalitional World

2018 ◽  
Author(s):  
Paul Chaisty ◽  
Nic Cheeseman ◽  
Timothy J. Power
Keyword(s):  
Coalition Formation ◽  
Cost Minimization ◽  
Analytical Framework ◽  
System Level ◽  
Current State ◽  
Key Concepts ◽  
Definition Of

This chapter summarizes the main parameters of coalitional presidentialism and the key concepts, definitions, explanatory frameworks, indicators, and propositions. It summarizes our understanding of coalitional presidentialism; the distinction between coalition formation and maintenance; the definition of coalitions; the multidimensional understanding of coalition management (the ‘presidential toolbox’); and an analytical framework that emphasizes the motivation of presidents to achieve cost minimization under constraints determined by system-level, coalition-level, and conjunctural factors. It also summarizes our main empirical findings: (1) the characteristics of presidential tools, (2) the substantive patterns of their deployment, (3) the factors that shape the costs of using these tools, (4) the actual (observed) costs of using them, and (5) the potential for imperfect substitutability of these tools. Finally, it concludes with some reflections on the current state of the research on comparative presidentialism.

Clonal Isolation of an Intermediate Pluripotent Stem Cell State

Stem Cells ◽  
2013 ◽  
Vol 31 (5) ◽  
pp. 918-927 ◽  
Author(s):  
Kuo-Hsuan Chang ◽  
Meng Li
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Cell State ◽  
Stem Cell State

HLF Expression Defines the Human Hematopoietic Stem Cell State.

Blood ◽  
2021 ◽  
Author(s):  
Bernhard Lehnertz ◽  
Jalila Chagraoui ◽  
Tara MacRae ◽  
Elisa Tomellini ◽  
Sophie Corneau ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Fetal Liver ◽  
Cell Activity ◽  
Mouse Strains ◽  
Marker Genes ◽  
Hematopoietic Stem ◽  
Cell State ◽  
Human Hscs ◽  
Stem Cell State

Hematopoietic stem cells (HSCs) sustain blood cell homeostasis throughout life and can regenerate all blood lineages following transplantation. Despite this clear functional definition, highly enriched isolation of human HSCs can currently only be achieved through combinatorial assessment of multiple surface antigens. While several transgenic HSC reporter mouse strains have been described, no analogous approach to prospectively isolate human HSCs has been reported. To identify genes with the most selective expression in human HSCs, we profiled population- and single-cell transcriptomes of un-expanded and ex vivo cultured cord blood-derived HSPCs as well as peripheral blood, adult bone marrow, and fetal liver. Based on these analyses, we propose the master transcription factor HLF (Hepatic Leukemia Factor) as one of the most specific HSC marker genes. To directly track its expression in human hematopoietic cells, we developed a genomic HLF reporter strategy, capable of selectively labeling the most immature blood cells based on a single engineered parameter. Most importantly, HLF-expressing cells comprise all of the stem cell activity in culture and in vivo during serial transplantation. Taken together, these results experimentally establish HLF as a defining gene of the human hematopoietic stem cell state and outline a new approach to continuously mark these cells with high fidelity.

scholarly journals Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division

2018 ◽  
Vol 32 (23-24) ◽  
pp. 1550-1561 ◽  
Author(s):  
Hideyuki Komori ◽  
Krista L. Golden ◽  
Taeko Kobayashi ◽  
Ryoichiro Kageyama ◽  
Cheng-Yu Lee
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Neural Stem Cell ◽  
Gene Control ◽  
Cell State ◽  
Stem Cell Division ◽  
Stem Cell State

scholarly journals Limit theorems for some branching measure-valued processes

2017 ◽  
Vol 49 (2) ◽  
pp. 549-580 ◽  
Author(s):  
Bertrand Cloez
Keyword(s):  
Continuous Time ◽  
Limit Theorems ◽  
Particle System ◽  
Large Population ◽  
Empirical Measure ◽  
Spatial Motion ◽  
Auxiliary Process ◽  
Discrete Population ◽  
A Cell ◽  
Fragmentation Equation

AbstractWe consider a particle system in continuous time, a discrete population, with spatial motion, and nonlocal branching. The offspring's positions and their number may depend on the mother's position. Our setting captures, for instance, the processes indexed by a Galton–Watson tree. Using a size-biased auxiliary process for the empirical measure, we determine the asymptotic behaviour of the particle system. We also obtain a large population approximation as a weak solution of a growth-fragmentation equation. Several examples illustrate our results. The main one describes the behaviour of a mitosis model; the population is size structured. In this example, the sizes of the cells grow linearly and if a cell dies then it divides into two descendants.

scholarly journals Author response: A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation

2017 ◽  
Author(s):  
Meng Amy Li ◽  
Paulo P Amaral ◽  
Priscilla Cheung ◽  
Jan H Bergmann ◽  
Masaki Kinoshita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
State Transition ◽  
De Novo ◽  
Author Response ◽  
Cell State ◽  
A Cell

scholarly journals MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming

2021 ◽  
Author(s):  
Alexandre Gaspar-Maia ◽  
Wazim Mohammed Ismail ◽  
Amelia Mazzone ◽  
Jagneet Kaur ◽  
Stephanie Safgren ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Histone Variants ◽  
Cellular Reprogramming ◽  
Negative Regulator ◽  
Cellular Heterogeneity ◽  
Enhancer Activity ◽  
Active Enhancer ◽  
A Cell ◽  
Cell Type Specific

Abstract Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined ‘macroH2A-Bound Enhancers’, that negatively modulate enhancer activity. We find macroH2A variants enriched at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and its repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling, we show that the loss of macroH2A2 leads to increased cellular heterogeneity that may help to explain the role of macroH2A variants in defining oncogenic transcriptional dependencies.

scholarly journals Wnt Activity and Cell Proliferation Are Coupled to Extracellular Vesicle Release in Multiple Organoid Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Gyöngyvér Orsolya Sándor ◽  
András Áron Soós ◽  
Péter Lörincz ◽  
Lívia Rojkó ◽  
Tünde Harkó ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Disease Diagnosis ◽  
Extracellular Vesicle ◽  
Cellular Heterogeneity ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Tools ◽  
Proliferating Cells ◽  
Pathway Activation ◽  
A Cell ◽  
Potential Tool

Extracellular vesicles (EV) are considered as a potential tool for early disease diagnosis; however, factors modifying EV release remain partially unknown. By using patient-derived organoids that capture the cellular heterogeneity of epithelial tissues, here we studied the connection between the Wnt-producing microniche and EV secretion in multiple tissues. Although nearly all cells in pancreatic ductal (PD) and pancreatic ductal adenocarcinoma (PDAC) samples expressed porcupine (PORCN), an enzyme critical for Wnt secretion, only a subpopulation of lung bronchiolar (NL) and lung adenocarcinoma (LUAD) organoid cells produced active Wnt. The microniche for proliferating cells was shaped not only by PORCN + cells in NL and LUAD organoids but also by fibroblast-derived EVs. This effect could be blocked by using Wnt secretion inhibitors. Whereas inhibiting Wnt secretion in PD NL or LUAD organoids critically changed both cell proliferation and EV release, these were uncoupled from each other in PDAC. Sorting for CD133 identified a cell population in the LUAD microniche that produced organoids with a high percentage of PORCN + and proliferating cells and an elevated EV secretion, which may explain that CD133 marks LUAD cells with malignant behavior. Collectively, we show here that high cell proliferation rate, induced by Wnt pathway activation, is coupled to a higher EV release, a critical finding that may be considered when developing EV-based diagnostic tools.

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