scholarly journals Hierarchical Tissue Organization as a General Mechanism to Limit Somatic Evolution

2017 ◽  
Vol 112 (3) ◽  
pp. 284a
Author(s):  
Imre Derenyi ◽  
Gergely J. Szollosi
Keyword(s):  
General Mechanism ◽  
Somatic Evolution ◽  
Tissue Organization

scholarly journals Trade-off between reducing mutational load and increasing commitment to differentiation determines tissue organization

2020 ◽  
Author(s):  
Márton Demeter ◽  
Imre Derényi ◽  
Gergely J. Szöllősi
Keyword(s):  
Tumor Suppressor Genes ◽  
Mutation Accumulation ◽  
Specific Level ◽  
Trade Off ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Copy Numbers ◽  
Magnitude Variation ◽  
Species Specific ◽  
Risk Of Cancer

AbstractSpecies-specific differences control cancer risk across orders of magnitude variation in body size and lifespan, e.g., by varying the copy numbers of tumor suppressor genes. It is unclear, however, how different tissues within an organism can control somatic evolution despite being subject to markedly different constraints but sharing the same genome. Hierarchical differentiation, characteristic of self-renewing tissues, can restrain somatic evolution both by limiting divisional load, thereby reducing mutation accumulation, and by increasing the cells’ commitment to differentiation, which can “wash out” mutants. Here, we explore the organization of hierarchical tissues that have evolved to limit their lifetime risk of cancer to a tissue-specific level. Analytically estimating the likelihood of cancer, we demonstrate that a trade-off exists between mutation accumulation and the strength of washing out. This result explains the differences in the organization of widely different hierarchically differentiating tissues, such as the colon and the blood.

scholarly journals A compartment size dependent selective threshold limits mutation accumulation in hierarchical tissues

2019 ◽  
Author(s):  
Daniel Grajzel ◽  
Imre Derenyi ◽  
Gergely J Szollosi
Keyword(s):  
Selective Advantage ◽  
Cell Number ◽  
Significant Determinant ◽  
Size Dependent ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Tissue Size ◽  
Risk Of Cancer ◽  
Proliferative Advantage ◽  
Fundamental Mechanism

Cancer is a genetic disease fueled by somatic evolution. Hierarchical tissue organization can slow somatic evolution by two qualitatively different mechanisms: by cell differentiation along the hierarchy "washing out" harmful mutations (Nowak et al. 2003, Werner et al. 2013) and by limiting the number of cell divisions required to maintain a tissue (Derenyi and Szollosi 2017). Here we explore the effects of compartment size on somatic evolution in hierarchical tissues by considering cell number regulation that acts on cell division rates such that the number of cells in the tissue has the tendency to return to its desired homeostatic value. Introducing mutants with a proliferative advantage we demonstrate the existence of a third fundamental mechanism by which hierarchically organized tissues are able to slow down somatic evolution. We show that tissue size regulation leads to the emergence of a threshold proliferative advantage, below which mutants cannot persist. We find that the most significant determinant of the threshold selective advantage is compartment size, with the threshold being higher the smaller the compartment. Our results demonstrate that in sufficiently small compartments even mutations that confer substantial proliferative advantage cannot persist, but are expelled from the tissue by differentiation along the hierarchy. The resulting selective barrier can significantly slow down somatic evolution and reduce the risk of cancer by limiting the accumulation of mutations that increase the proliferation of cells.

scholarly journals A generalized theory of somatic evolution

2018 ◽  
Author(s):  
Andrii Rozhok ◽  
James DeGregori
Keyword(s):  
Stem Cell ◽  
Current Knowledge ◽  
Age Distribution ◽  
Experimental Studies ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Theoretical Idea ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Multi Stage

AbstractThe modern Multi-Stage Model of Carcinogenesis (MMC) was developed in the 1950s through the ‘70s and postulated carcinogenesis as a process of rounds of Darwinian selection favoring progressively more malignant cell phenotypes. Through this period, almost nothing was known about driver mutations in cancers. Also, stem cells and cellular tissue organization were poorly characterized. The general multi-stage process was later confirmed by experimental studies, and cancer risk and incidence has been explained as primarily a function of mutation occurrence. However, the MMC has never been formally tested for its ability to account for current knowledge about cancer evolution. In particular, different numbers of cancer drivers required for different cancers and vast discrepancies in the organization of stem cell compartments for different tissues appear inconsistent with the very similar age distribution of the vast majority of cancers. In this regard, the initial theoretical idea underlying MMC is often over-interpreted with little connection to modern evidence, and a general theory of somatic evolution still does not exist. In this study, we applied Monte Carlo modeling and demonstrated the effect of various parameters, such as mutation rate, mutation effects and cell division, on the MMC performance. Our modeling demonstrates that the MMC requires considerable modification in order to describe cancer incidence. We elucidate the required conditions for how somatic cell selection should operate within the MMC in order to explain modern data on stem cell clonality and cancer, and propose a generalized theory of somatic evolution based on these results.

scholarly journals A compartment size-dependent selective threshold limits mutation accumulation in hierarchical tissues

2020 ◽  
Vol 117 (3) ◽  
pp. 1606-1611 ◽  
Author(s):  
Dániel Grajzel ◽  
Imre Derényi ◽  
Gergely J. Szöllősi
Keyword(s):  
Selective Advantage ◽  
Cell Number ◽  
Significant Determinant ◽  
Size Dependent ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Tissue Size ◽  
Risk Of Cancer ◽  
Proliferative Advantage ◽  
Fundamental Mechanism

Cancer is a genetic disease fueled by somatic evolution. Hierarchical tissue organization can slow somatic evolution by two qualitatively different mechanisms: by cell differentiation along the hierarchy “washing out” harmful mutations and by limiting the number of cell divisions required to maintain a tissue. Here we explore the effects of compartment size on somatic evolution in hierarchical tissues by considering cell number regulation that acts on cell division rates such that the number of cells in the tissue has the tendency to return to its desired homeostatic value. Introducing mutants with a proliferative advantage, we demonstrate the existence of a third fundamental mechanism by which hierarchically organized tissues are able to slow down somatic evolution. We show that tissue size regulation leads to the emergence of a threshold proliferative advantage, below which mutants cannot persist. We find that the most significant determinant of the threshold selective advantage is compartment size, with the threshold being higher the smaller the compartment. Our results demonstrate that, in sufficiently small compartments, even mutations that confer substantial proliferative advantage cannot persist, but are expelled from the tissue by differentiation along the hierarchy. The resulting selective barrier can significantly slow down somatic evolution and reduce the risk of cancer by limiting the accumulation of mutations that increase the proliferation of cells.

scholarly journals Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations

2017 ◽  
Author(s):  
Imre Derényi ◽  
Gergely J. Szöllősi
Keyword(s):  
Somatic Mutations ◽  
Cell Types ◽  
General Mechanism ◽  
Analytical Relationship ◽  
Tissue Organization ◽  
Large Numbers ◽  
Dynamical Parameters ◽  
Prevention Of Cancer ◽  
Risk Of Cancer ◽  
Tissue Specific Stem Cells

AbstractHow can tissues generate large numbers of cells, yet keep the divisional load (the number of divisions along cell lineages) low in order to curtail the accumulation of somatic mutations and reduce the risk of cancer? To answer the question we consider a general model of hierarchically organized self-renewing tissues and show that the lifetime divisional load of such a tissue is independent of the details of the cell differentiation processes, and depends only on two structural and two dynamical parameters. Our results demonstrate that a strict analytical relationship exists between two seemingly disparate characteristics of self-renewing tissues: divisional load and tissue organization. Most remarkably, we find that a sufficient number of progressively slower dividing cell types can be almost as efficient in minimizing the divisional load, as non-renewing tissues. We argue that one of the main functions of tissue-specific stem cells and differentiation hierarchies is the prevention of cancer.

Going Beyond 3-D Imaging: Automated 3-D Montaged image Analysis of Cytological Specimens

1996 ◽  
Vol 54 ◽  
pp. 282-283
Author(s):  
Badrinath Roysam ◽  
Hakan Ancin ◽  
Douglas E. Becker ◽  
Robert W. Mackin ◽  
Matthew M. Chestnut ◽  
...  
Keyword(s):  
Image Analysis ◽  
Structural Changes ◽  
Sampling Methods ◽  
Spatial Clustering ◽  
Three Dimensional ◽  
Field Of View ◽  
Cell Counting ◽  
Depth Of Field ◽  
Tissue Cell ◽  
Tissue Organization

This paper summarizes recent advances made by this group in the automated three-dimensional (3-D) image analysis of cytological specimens that are much thicker than the depth of field, and much wider than the field of view of the microscope. The imaging of thick samples is motivated by the need to sample large volumes of tissue rapidly, make more accurate measurements than possible with 2-D sampling, and also to perform analysis in a manner that preserves the relative locations and 3-D structures of the cells. The motivation to study specimens much wider than the field of view arises when measurements and insights at the tissue, rather than the cell level are needed.The term “analysis” indicates a activities ranging from cell counting, neuron tracing, cell morphometry, measurement of tracers, through characterization of large populations of cells with regard to higher-level tissue organization by detecting patterns such as 3-D spatial clustering, the presence of subpopulations, and their relationships to each other. Of even more interest are changes in these parameters as a function of development, and as a reaction to external stimuli. There is a widespread need to measure structural changes in tissue caused by toxins, physiologic states, biochemicals, aging, development, and electrochemical or physical stimuli. These agents could affect the number of cells per unit volume of tissue, cell volume and shape, and cause structural changes in individual cells, inter-connections, or subtle changes in higher-level tissue architecture. It is important to process large intact volumes of tissue to achieve adequate sampling and sensitivity to subtle changes. It is desirable to perform such studies rapidly, with utmost automation, and at minimal cost. Automated 3-D image analysis methods offer unique advantages and opportunities, without making simplifying assumptions of tissue uniformity, unlike random sampling methods such as stereology.12 Although stereological methods are known to be statistically unbiased, they may not be statistically efficient. Another disadvantage of sampling methods is the lack of full visual confirmation - an attractive feature of image analysis based methods.

Further Evidence for Energy Landscape Flattening in the Superionic Argyrodites Li6+xP1−xMxS5I (M = Si, Ge, Sn)

2019 ◽  
Author(s):  
Saneyuki Ohno ◽  
Bianca Helm ◽  
Till Fuchs ◽  
Georg Dewald ◽  
Marvin Kraft ◽  
...  
Keyword(s):  
Solid State ◽  
Activation Barrier ◽  
Energy Landscape ◽  
General Mechanism ◽  
Ionic Conductors ◽  
Energy Storage Devices ◽  
Ion Conductor ◽  
Storage Devices ◽  
Open Questions ◽  
Sudden Decrease

<p>All-solid-state batteries are promising candidates for next-generation energy storage devices. Although the list of candidate materials for solid electrolytes has grown in the past decade, there are still many open questions concerning the mechanisms behind ionic migration in materials. In particular, the lithium thiophosphate family of materials has shown very promising properties for solid-state battery applications. Recently, the Ge-substituted Li<sub>6</sub>PS<sub>5</sub>I argyrodite was shown to be a very fast Li-ion conductor, despite the poor ionic conductivity of the unsubstituted Li<sub>6</sub>PS<sub>5</sub>I. Therein, the conductivity was enhanced by over three orders of magnitude due to the emergence of I<sup>−</sup>/S<sup>2−</sup>exchange, <i>i.e.</i>site-disorder, which led to a sudden decrease of the activation barrier with a concurrent flattening of the energy landscapes. Inspired by this work, two series of elemental substitutions in Li<sub>6+<i>x</i></sub>P<sub>1−<i>x</i></sub><i>M<sub>x</sub></i>S<sub>5</sub>I (<i>M</i>= Si and Sn) were investigated in this study and compared to the Ge-analogue. A sharp reduction in the activation energy was observed at the same <i>M</i><sup>4+</sup>/P<sup>5+</sup>composition as previously found in the Ge-analogue, suggesting a more general mechanism at play. Furthermore, structural analyses with X-ray and neutron diffraction indicate that similar changes in the Li-sublattice occur despite a significant variation in the size of the substituents, suggesting that in the argyrodites, the lithium substructure is most likely influenced by the occurring Li<sup>+</sup>– Li<sup>+</sup>interactions. This work provides further evidence that the energy landscape of ionic conductors can be tailored by inducing local disorder.</p>

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