Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity

Frontiers in Oncology, Journal Year: 2018, Volume and Issue: 8

Published: March 6, 2018

It is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we instead focus on alternate mechanisms – those without such as phenotypic plasticity stochastic cell-to-cell variability also evade attacks by giving rise drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria recently garnered attention cancer. We draw a parallel between bacterial against androgen deprivation therapy prostate cancer (PCa), the primary standard care for metastatic disease. illustrate how consequent mutation-independent or non-genetic heterogeneity possibly driven protein conformational dynamics stochastically give independence PCa, suggest dynamic should be considered devising therapeutic dosing strategies designed treat manage PCa.

Language: Английский

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Emergent Subpopulation Behavior Uncovered with a Community Dynamic Metabolic Model of Escherichia coli Diauxic Growth

mSystems, Journal Year: 2019, Volume and Issue: 4(1)

Published: Jan. 14, 2019

Microbes have adapted to greatly variable environments in order survive both short-term perturbations and permanent changes. A classical yet still actively studied example of adaptation dynamic is the diauxic shift Escherichia coli, which cells grow on glucose until its exhaustion then transition using previously secreted acetate. Here we tested different hypotheses concerning nature this by metabolic modeling. To reach goal, developed an open source modeling framework integrating models (ordinary differential equation systems) with structural (metabolic networks) can take into account behavior multiple subpopulations smooth flux transitions between time points. We used model shift, first a single E. coli whose state represents overall population average community two subpopulations, each growing exclusively one carbon (glucose or acetate). After introduction environment-dependent function that determined balance our generated predictions are strong agreement published data. Our results thus support recent experimental evidence diauxie, rather than coordinated would be emergent pattern individual differentiating for optimal growth substrates. This work offers new perspective use investigate heterogeneity dynamics. The proposed approach easily applied other biological systems composed metabolically distinct, interconverting could extended include single-cell-level stochasticity. IMPORTANCE diauxie fundamental adaptation, phenomenon not completely understood. Further insight process achieved computational methods. present captures as property subpopulation dynamics monocultures. Without fine-tuning parameters core model, good suggest single-organism only approximate population, therefore offering such approaches. provide general more-complex

Language: Английский

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Trade-offs between gene expression, growth and phenotypic diversity in microbial populations

Current Opinion in Biotechnology, Journal Year: 2019, Volume and Issue: 62, P. 29 - 37

Published: Oct. 1, 2019

Bacterial cells have a limited number of resources that can be allocated for gene expression. The intracellular competition these has an impact on the cell physiology. Bacteria evolved mechanisms to optimize resource allocation in variety scenarios, showing trade-off between used maximise growth (e.g. ribosome synthesis) and rest cellular functions. Limitations expression also play role generating phenotypic diversity, which is advantageous fluctuating environments, at expenses decreasing rates. Our current understanding trade-offs exploited biotechnological applications benefiting from selective manipulation resources.

Language: Английский

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Modeling cell population dynamics

In Silico Biology, Journal Year: 2018, Volume and Issue: 13(1-2), P. 21 - 39

Published: Dec. 11, 2018

Quantitative modeling is quickly becoming an integral part of biology, due to the ability mathematical models and computer simulations generate insights predict behavior living systems. Single-cell can be incapable or misleading for inferring population dynamics, as they do not consider interactions between cells via metabolites physical contact, nor competition limited resources such nutrients space. Here we examine methods that are commonly used model simulate cell populations. First, cover simple where analytic solutions available, then move on more complex scenarios computational required. Overall, present a summary describe which may aid future development highlights importance in biology.

Language: Английский

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Intrinsic and extrinsic noise of gene expression in lineage trees

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Jan. 24, 2019

Cell-to-cell heterogeneity is driven by stochasticity in intracellular reactions and the population dynamics. While these sources are usually studied separately, we develop an agent-based framework that accounts for both factors while tracking every single cell of a growing population. Apart from common intrinsic variability, also predicts extrinsic noise without need to introduce fluctuating rate constants. Instead, fluctuations explained cycle differences age. We provide explicit formulas quantify mean molecule numbers, statistics two-colour experiments. find differ significantly depending on experimental setup used observe cells. illustrate this fact using (i) averages over isolated lineage tracked many generations as observed mother machine, (ii) snapshots with known ages recorded time-lapse microscopy, (iii) unknown measured static images or flow cytometry. Applying method models stochastic gene expression feedback regulation elucidates lineages, compared snapshot data, can overestimate number molecules, but underestimate have qualitatively different sensitivities fluctuations.

Language: Английский

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Order Through Disorder: The Characteristic Variability of Systems

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: March 20, 2020

Randomness characterizes many processes in nature, and therefore its importance cannot be overstated. In the present study, we investigate examples of randomness found various fields, to underlie fundamental processes. The fields address include physics, chemistry, biology (biological systems from genes whole organs), medicine, environmental science. Through chosen examples, explore seemingly paradoxical nature life demonstrate that is preferred under specific conditions. Furthermore, certain conditions, promoting or making use variability-associated parameters may necessary for improving function systems.

Language: Английский

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Extrinsic Noise and Heavy-Tailed Laws in Gene Expression

Physical Review Letters, Journal Year: 2020, Volume and Issue: 124(10)

Published: March 11, 2020

Noise in gene expression is one of the hallmarks life at molecular scale. Here we derive analytical solutions to a set models describing mechanisms underlying transcription DNA into RNA. Our ansatz allows us incorporate effects extrinsic noise---encompassing factors external individual gene---and discuss ramifications for heterogeneity product abundance that has been widely observed single cell data. Crucially, are able show heavy-tailed distributions RNA copy numbers cannot result from intrinsic stochasticity alone, but must instead reflect sources variability.

Language: Английский

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Scale‐Free Biology: Integrating Evolutionary and Developmental Thinking

BioEssays, Journal Year: 2020, Volume and Issue: 42(8)

Published: June 14, 2020

Abstract When the history of life on earth is viewed as a cell division, all becomes single lineage. The growth and differentiation this lineage in reciprocal interaction with its environment can be developmental process; hence evolution also seen development earth. Here, reviewing field, some potentially fruitful research directions suggested by change perspective are highlighted. Variation selection become, for example, bidirectional information flows between scales, while notions “cooperation” “competition” become scale relative. language communication, inference, processing more useful than causation to describe interactions both homogeneous heterogeneous living systems at any scale. Emerging scale‐free theoretical frameworks such predictive coding active inference provide conceptual tools reconceptualizing biology study unified, multiscale dynamical system.

Language: Английский

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Topological signatures in regulatory network enable phenotypic heterogeneity in small cell lung cancer

eLife, Journal Year: 2021, Volume and Issue: 10

Published: March 17, 2021

Phenotypic (non-genetic) heterogeneity has significant implications for the development and evolution of organs, organisms, populations. Recent observations in multiple cancers have unraveled role phenotypic driving metastasis therapy recalcitrance. However, origins such are poorly understood most cancers. Here, we investigate a regulatory network underlying small cell lung cancer, devastating disease with no molecular targeted therapy. Discrete continuous dynamical simulations this reveal its multistable behavior that can explain co-existence four experimentally observed phenotypes. Analysis topology uncovers multistability emerges from two teams players mutually inhibit each other, but members team activate one another, forming ‘toggle switch’ between teams. Deciphering these topological signatures cancer-related networks unravel their ‘latent’ design principles offer rational approach to characterize tumor.

Language: Английский

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Biphasic Cell-Size and Growth-Rate Homeostasis by Single Bacillus subtilis Cells

Current Biology, Journal Year: 2020, Volume and Issue: 30(12), P. 2238 - 2247.e5

Published: May 14, 2020

The growth rate of single bacterial cells is continuously disturbed by random fluctuations in biosynthesis rates and deterministic cell-cycle events, such as division, genome duplication, septum formation. It not understood whether, how, bacteria reject these growth-rate disturbances. Here, we quantified constitutive protein expression dynamics Bacillus subtilis a function progression. We found that, even though at the population level exponential, close inspection cell cycle thousands reveals systematic deviations from exponential growth. Newborn display varying that depend on their size. When they divide, variation has decreased, have become birth size independent. Thus, indeed compensate for disturbances achieve homeostasis. Protein synthesis displayed correlated, biphasic to division. During first phase variable duration, absolute were approximately constant behaved sizers. In second phase, increased, behavior exhibited characteristics timer strategy. These findings demonstrate just like homeostasis, homeostasis an inherent property achieved cell-cycle-dependent adjustments

Language: Английский

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